RESUMO
Accurate diagnosis and effective treatment of tumors remain significant clinical challenges. While fluorescence imaging is essential for tumor detection, it has limitations in terms of specificity, penetration depth, and emission wavelength. Here, we report a novel glutathione (GSH)-responsive peptide self-assembly excimer probe (pSE) that optimizes two-photon tumor imaging and self-assisted counteraction of the cisplatin resistance in cancer cells. The GSH-responsive self-assembly of pSE induces a monomer-excimer transition of coumarin, promoting a near-infrared redshift of fluorescence emission under two-photon excitation. This process enhances penetration depth and minimizes interference from biological autofluorescence. Moreover, the intracellular self-assembly of pSE impacts GSH homeostasis, modulates relevant signaling pathways, and significantly reduces GSTP1 expression, resulting in decreased cisplatin efflux in cisplatin-resistant cancer cells. The proposed self-assembled excimer probe not only distinguishes cancer cells from normal cells but also enhances the efficacy of cisplatin chemotherapy, offering significant potential in tumor diagnosis and overcoming cisplatin-resistant tumors.
Assuntos
Antineoplásicos , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Glutationa , Peptídeos , Cisplatino/farmacologia , Cisplatino/química , Humanos , Peptídeos/química , Peptídeos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Glutationa/metabolismo , Glutationa/química , Fótons , Imagem Óptica , Corantes Fluorescentes/química , Cumarínicos/química , Cumarínicos/farmacologia , Linhagem Celular TumoralRESUMO
Tumor immunotherapy has become a research hotspot in cancer treatment, with macrophages playing a crucial role in tumor development. However, the tumor microenvironment restricts macrophage functionality, limiting their therapeutic potential. Therefore, modulating macrophage function and polarization is essential for enhancing tumor immunotherapy outcomes. Here, a supramolecular peptide amphiphile drug-delivery system (SPADS) is utilized to reprogram macrophages and reshape the tumor immune microenvironment (TIM) for immune-based therapies. The approach involved designing highly specific SPADS that selectively targets surface receptors of M2-type macrophages (M2-Mφ). These targeted peptides induced M2-Mφ repolarization into M1-type macrophages by dual inhibition of endoplasmic reticulum and oxidative stresses, resulting in improved macrophagic antitumor activity and immunoregulatory function. Additionally, TIM reshaping disrupted the immune evasion mechanisms employed by tumor cells, leading to increased infiltration, and activation of immune cells. Furthermore, the synergistic effect of macrophage reshaping and anti-PD-1 antibody (aPD-1) therapy significantly improved the immune system's ability to recognize and eliminate tumor cells, thereby enhancing tumor immunotherapy efficacy. SPADS utilization also induced lung metastasis suppression. Overall, this study demonstrates the potential of SPADS to drive macrophage reprogramming and reshape TIM, providing new insights, and directions for developing more effective immunotherapeutic approaches in cancer treatment.
Assuntos
Neoplasias da Mama , Imunoterapia , Nanosferas , Peptídeos , Microambiente Tumoral , Macrófagos Associados a Tumor , Microambiente Tumoral/efeitos dos fármacos , Imunoterapia/métodos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Animais , Nanosferas/química , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Peptídeos/química , Peptídeos/farmacologia , Feminino , Camundongos , Linhagem Celular Tumoral , Humanos , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Substrate-based ablation can treat uninducible or hemodynamically instability scar-related ventricular tachycardia (VT). However, whether a correlation exists between the critical VT isthmus and late activation zone (LAZ) during sinus rhythm (SR) is unknown. OBJECTIVE: To demonstrate the structural and functional properties of abnormal substrates and analyze the link between the VT circuit and abnormal activity during SR. METHODS: Thirty-six patients with scar-related VT (age, 50.0 ± 13.7 years and 86.1% men) who underwent VT ablation were reviewed. The automatic rhythmia ultrahigh resolution mapping system was used for electroanatomic substrate mapping. The clinical characteristics and mapping findings, particularly the LAZ characteristics during SR and VT, were analyzed. To determine the association between the LAZ during the SR and VT circuits, the LAZ was defined as five activation patterns: entrance, exit, core, blind alley, and conduction barrier. RESULTS: Forty-five VTs were induced in 36 patients, 91.1% of which were monomorphic. The LAZ of all patients was mapped during the SR and VT circuits, and the consistency of the anatomical locations of the LAZ and VT circuits was analyzed. Using the ultrahigh resolution mapping system, interconversion patterns, including the bridge, T, puzzle, maze, and multilayer types, were identified. VT ablation enabled precise ablation of abnormal late potential conduction channels. CONCLUSION: Five interconversion patterns of the LAZ during the SR and VT circuits were summarized. These findings may help formulate more precise substrate-based ablation strategies for scar-related VT and shorter procedure times.
Assuntos
Ablação por Cateter , Taquicardia Ventricular , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Feminino , Cicatriz , Técnicas Eletrofisiológicas Cardíacas , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/cirurgia , Frequência Cardíaca , Fatores de Tempo , Ablação por Cateter/efeitos adversosRESUMO
It is challenging to construct high-performing excimer-based luminescent analytic tools at low molecular concentrations. We report that enzyme-instructed self-assembly (EISA) enables the monomer-excimer transition of a coumarin dye (Cou) at low molecular concentrations, and the resulting higher ordered luminescent supramolecular assemblies (i.e., nanofibers) efficiently record the spatiotemporal details of alkaline phosphatase (ALP) activity inâ vitro and inâ vivo. Cou was conjugated to short self-assembly peptides with a hydrophilic ALP-responsive group. By ALP triggering, EISA actuated a nanoparticles-nanofibers transition at low peptide concentrations followed by monomer-excimer transition of Cou. Analysis of structure-property relationships revealed that the self-assembly motif was a prerequisite for peptides to induce the monomer-excimer transition of Cou. Luminescent supramolecular nanofibers of pYD (LSN-pYD) illuminated the intercellular bridge of cancer cells and distinguished cancer cells (tissues) from normal cells (tissues) efficiently and rapidly, promising potential use for the early diagnosis of cancer. This work extends the functions of EISA and provides a new application of supramolecular chemistry.
Assuntos
Fosfatase Alcalina/metabolismo , Cumarínicos/análise , Ensaio de Imunoadsorção Enzimática , Corantes Fluorescentes/análise , Luminescência , Imagem Óptica , Fosfatase Alcalina/química , Cumarínicos/metabolismo , Corantes Fluorescentes/metabolismo , Células HeLa , Humanos , Substâncias Macromoleculares/análise , Substâncias Macromoleculares/metabolismo , Estrutura Molecular , Nanofibras/análiseRESUMO
We herein describe the tandem molecular self-assembly of a peptide derivative (1) that is controlled by a combination of enzymatic and chemical reactions. In phosphate-buffered saline (PBS), compound 1 self-assembles first into nanoparticles by phosphatase and then into nanofibers by glutathione. Liver cancer cells exhibit higher concentrations of both phosphatase and GSH than normal cells. Therefore, the tandem self-assembly of 1 also occurs in the liver cancer cell lines HepG2 and QGY7703; compound 1 first forms nanoparticles around the cells and then forms nanofibers inside the cells. Owing to this self-assembly mechanism, compound 1 exhibits large ratios for cellular uptake and inhibition of cell viability between liver cancer cells and normal liver cells. We envision that using both extracellular and intracellular reactions to trigger tandem molecular self-assembly could lead to the development of supramolecular nanomaterials with improved performance in cancer diagnostics and therapy.
Assuntos
Peptídeos/metabolismo , Fosfatase Alcalina/metabolismo , Linhagem Celular Tumoral , Glutationa/química , Células Hep G2 , Humanos , Microscopia Confocal , Nanofibras/química , Nanopartículas/química , Peptídeos/químicaRESUMO
Nuclear delivery and accumulation are very important for many anticancer drugs that interact with DNA or its associated enzymes in the nucleus. However, it is very difficult for neutrally and negatively charged anticancer drugs such as 10-hydroxycamptothecine (HCPT). Here we report a simple strategy to construct supramolecular nanomedicines for nuclear delivery of dual synergistic anticancer drugs. Our strategy utilizes the coassembly of a negatively charged HCPT-peptide amphiphile and the positively charged cisplatin. The resulting nanomaterials behave as the "Trojan Horse" that transported soldiers (anticancer drugs) across the walls of the castle (cell and nucleus membranes). Therefore, they show improved inhibition capacity to cancer cells including the drug resistant cancer cell and promote the synergistic tumor suppression property in vivo. We envision that our strategy of constructing nanomaterials by metal chelation would offer new opportunities to develop nanomedicines for combination chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Cisplatino/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Substâncias Macromoleculares/química , Camundongos , Estrutura Molecular , Nanomedicina , Neoplasias/patologiaRESUMO
We report in this study on optimized ratiometric fluorescent probes by peptide self-assembly. The resulting self-assembled nanoprobes show extraordinary stability in aqueous solutions and extremely low background fluorescence in buffer solutions. Our optimized probes with much bigger ratiometric fluorescence ratios also show an enhanced cellular uptake, lower background noise, and much brighter fluorescence signal in the cell experiment. Our study provides a versatile and very useful strategy to design and produce fluorescent probes with better performance.
Assuntos
Corantes Fluorescentes/química , Peptídeos/química , Peptídeos/síntese química , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Hidrazinas/análise , Sulfeto de Hidrogênio/análise , Microscopia de Fluorescência , Estrutura MolecularRESUMO
The combination of an environment-sensitive fluorophore, 4-nitro-2,1,3-benzoxadiazole (NBD), and peptides have yielded supramolecular nanofibers with enhanced cellular uptake, brighter fluorescence, and significant fluorescence responses to external stimuli. We had designed and synthesized NBD-FFYEEGGH that can form supramolecular nanofibers and emit brighter than its counterpart of NBD-EEGGH without the self-assembling property. The nanofibers of NBD-FFYEEGGH could specifically bind to Cu(2+), leading to the formation of fluorescence quenched elongated nanofibers. This fluorescence quenching property was enhanced in self-assembling nanofibers and could be applied for detection of Cu(2+) in vitro and within cells. In a further step, an enzyme-cleavable DEVD peptide was placed between NBD-FFY and the copper binding tripeptide GGH. The resulting self-assembling peptide NBD-FFFDEVDGGH also showed strong fluorescence quenching to Cu(2+). Upon the enzymatic cleavage to remove the Cu(2+)-binding GGH tripeptide from the peptide, the fluorescence was restored. The cellular uptake of nanofibers was better than that of free molecules because of endocytosis. The supramolecular nanofibers with fluorescence turn-on property could therefore be applied for detection of caspase-3 activity in vitro and within cells. We believe that the combination of environment-sensitive fluorescence and fast responses of supramolecular nanostructures would lead to a useful platform to detect many important analytes.
Assuntos
Meio Ambiente , Corantes Fluorescentes/química , Nanofibras/química , Espectrometria de Fluorescência/métodos , Células HeLa , Humanos , Estrutura Secundária de ProteínaRESUMO
The enzyme tyrosinase could trigger the disassembly of peptide-based nanospheres, resulting in F-NMR signal turning on.
Assuntos
Monofenol Mono-Oxigenase/análise , Monofenol Mono-Oxigenase/metabolismo , Nanosferas/química , Ressonância Magnética Nuclear Biomolecular , Peptídeos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flúor/química , Flúor/metabolismo , Camundongos , Conformação Molecular , Células NIH 3T3 , Nanosferas/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
Doxorubicin, an anthracycline chemotherapeutic agent, elicits a deleterious cardiotoxicity known as doxorubicin-induced cardiomyopathy (DIC) that circumscribes its chemotherapy utility for malignancies. Recent empirical evidence implicates ferroptosis, an iron-dependent form of regulated cell death, as playing a pivotal role in the pathogenesis of DIC. We postulated that anti-ferroptosis agents may constitute a novel therapeutic strategy for mitigating DIC. To test this hypothesis, we engineered baicalin-peptide supramolecular self-assembled nanofibers designed to selectively target the angiotensin II type I receptor (AT1R), which is upregulated in doxorubicin-damaged cardiomyocytes. This enabled targeted delivery of baicalin, a natural antioxidant compound, to inhibit ferroptosis in the afflicted myocardium. In vitro, the nanofibers ameliorated cardiomyocyte death by attenuating peroxide accumulation and suppressing ferroptosis. In a murine model of DIC, AT1R-targeted baicalin delivery resulted in efficacious cardiac accumulation and superior therapeutic effects compared to systemic administration. This investigation delineates a promising framework for developing targeted therapies that alleviate doxorubicin-induced cardiotoxicity by inhibiting the ferroptosis pathway in cardiomyocytes.
Assuntos
Ferroptose , Flavonoides , Nanofibras , Animais , Camundongos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Doxorrubicina , Miócitos Cardíacos , Peptídeos/uso terapêuticoRESUMO
Microvascular dysfunction following myocardial infarction exacerbates coronary flow obstruction and impairs the preservation of ventricular function. The apelinergic system, known for its pleiotropic effects on improving vascular function and repairing ischemic myocardium, has emerged as a promising therapeutic target for myocardial infarction. Despite its potential, the natural apelin peptide has an extremely short circulating half-life. Current apelin analogs have limited receptor binding efficacy and poor targeting, which restricts their clinical applications. In this study, we utilized an enzyme-responsive peptide self-assembly technique to develop an enzyme-responsive small molecule peptide that adapts to the expression levels of matrix metalloproteinases in myocardial infarction lesions. This peptide is engineered to respond to the high concentration of matrix metalloproteinases in the lesion area, allowing for precise and abundant presentation of the apelin motif. The changes in hydrophobicity allow the apelin motif to self-assemble into a supramolecular multivalent peptide ligand-SAMP. This self-assembly behavior not only prolongs the residence time of apelin in the myocardial infarction lesion but also enhances the receptor-ligand interaction through increased receptor binding affinity due to multivalency. Studies have demonstrated that SAMP significantly promotes angiogenesis after ischemia, reduces cardiomyocyte apoptosis, and improves cardiac function. This novel therapeutic strategy offers a new approach to restoring coronary microvascular function and improving damaged myocardium after myocardial infarction.
Assuntos
Apelina , Infarto do Miocárdio , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Animais , Apelina/administração & dosagem , Apelina/metabolismo , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Humanos , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8+ T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.
Assuntos
Antígeno CD24 , Antígeno CD47 , Macrófagos , Peptídeos , Fagocitose , Transdução de Sinais , Antígeno CD47/metabolismo , Antígeno CD47/imunologia , Animais , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Camundongos , Fagocitose/efeitos dos fármacos , Antígeno CD24/metabolismo , Antígeno CD24/imunologia , Feminino , Humanos , Linhagem Celular Tumoral , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Camundongos Endogâmicos BALB C , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias da Mama/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Anticorpos/imunologia , Anticorpos/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
In pancreatic cancer (PC), surgical resection remains the sole curative option, albeit patients undergoing resection are susceptible to postoperative pancreatic fistula (PF) formation and tumor recurrence. An unmet need exists for a unified strategy capable of concomitantly averting PF and tumor relapse to mitigate morbidity in PC patients after surgery. Herein, an original dual crosslinked biological sealant hydrogel (methacrylate-hyaluronic acid-dopamine (MA-HA-DA) and sulfhydryl-hyaluronic acid-dopamine (SH-HA-DA)) was engineered as a drug depot and loaded with polydopamine-cloaked cytokine interleukin-15 and platelets conjugated with anti-TIGIT. In vitro analyses validated favorable tissue adhesion, cytocompatibility, and stability of the hydrogels. In a PF rodent model, the hydrogel effectively adhered to the pancreatic stump, sealing the severed pancreatic end and impeding post-operative elevations in amylase and lipase. In PC murine models, hydrogels potently stimulated CD8+ T and NK cells to deter residual tumor re-growth and distant metastasis. This innovative hydrogel strategy establishes a new framework for concomitant prevention of PF and PC recurrence.
Assuntos
Hidrogéis , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Fístula Pancreática/prevenção & controle , Ácido Hialurônico , Dopamina , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias , RecidivaRESUMO
Stem cell-based therapies have demonstrated significant potential for use in heart regeneration. An effective paradigm for heart repair in rodent and large animal models is the transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Despite this, the functional and phenotypical immaturity of 2D-cultured hiPSC-CMs, particularly their low electrical integration, poses a caveat for clinical translation. In this study, a supramolecular assembly of a glycopeptide containing a cell adhesion motif-RGD, and saccharide-glucose (Bio-Gluc-RGD) is designed to enable the 3D spheroid formation of hiPSC-CMs, promoting cell-cell and cell-matrix interactions that occur during spontaneous morphogenesis. HiPSC-CMs in spheroids are prone to be phenotypically mature and developed robust gap junctions via activation of the integrin/ILK/p-AKT/Gata4 pathway. Monodispersed hiPSC-CMs encapsulated in the Bio-Gluc-RGD hydrogel are more likely to form aggregates and, therefore, survive in the infarcted myocardium of mice, accompanied by more robust gap junction formation in the transplanted cells, and hiPSC-CMs delivered with the hydrogels also displayed angiogenic effect and anti-apoptosis capacity in the peri-infarct area, enhancing their overall therapeutic efficacy in myocardial infarction. Collectively, the findings illustrate a novel concept for modulating hiPSC-CM maturation by spheroid induction, which has the potential for post-MI heart regeneration.
Assuntos
Células-Tronco Pluripotentes Induzidas , Infarto do Miocárdio , Humanos , Camundongos , Animais , Miócitos Cardíacos/metabolismo , Glicopeptídeos/metabolismo , Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Oligopeptídeos/metabolismo , Diferenciação CelularRESUMO
Organelles are responsible for the efficient storage and transport of substances in living systems. A myriad of extracellular vesicles (EVs) acts as a bridge to exchange signaling molecules in cell-cell communication, and the highly dynamic tubulins and actins contribute to efficient intracellular substance transport. The inexhaustible cues of natural cargo delivery by organelles inspire researchers to explore the construction of biomimetic architectures for "smart" delivery carriers. Herein, we report a 10-hydroxycamptothecin (HCPT)-peptide conjugate HpYss that simulates the artificial EV-to-filament transformation process for precise liver cancer therapy. Under the sequential stimulus of extracellular alkaline phosphatase (ALP) and intracellular glutathione (GSH), HpYss proceeds via tandem self-assembly with a morphological transformation from nanoparticles to nanofibers. The experimental phase diagram elucidates the influence of ALP and GSH contents on the self-assembled nanostructures. In addition, the dynamic transformation of organelle-mimetic architectures that are formed by HpYss in HepG2 cells enables the efficient delivery of the anticancer drug HCPT to the nucleus, and the size-shape change from extracellular nanoparticles (50-100 nm) to intracellular nanofibers (4-9 nm) is verified to be of key importance for nuclear delivery. Nuclear targeting of HpYss amplifies apoptosis, thus significantly enhancing the inhibitory effect of HCPT (>10-fold) to HepG2 cells. Benefitting from the spatiotemporally controlled nanostructures, HpYss exhibited deep penetration, enhanced accumulation, and long-term retention in multicellular spheroid and xenograft models, potently abolishing liver tumor growth and preventing lung metastasis. We envision that our organelle-mimicking delivery strategy provides a novel paradigm for designing nanomedicine to cancer therapy.
RESUMO
The overproduction of reactive oxygen species (ROS) and burst of inflammation following cardiac ischemia-reperfusion (I/R) are the leading causes of cardiomyocyte injury. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS activity explicitly for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS production and induction of inflammation. Intense oxidative stress leads to sustained injury, necrosis, and apoptosis of cardiomyocytes. The damaged and necrotic cells can release danger-associated molecular patterns (DAMPs) that can cause the aggregation of immune cells by activating Toll-like receptor 4 (TLR4). These immune cells also promote ROS production by expressing NADPH oxidase. Finally, ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. In the present study, we designed and prepared an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and the rhein-peptide hydrogel (Rh-gel). The co-assembled hydrogel efficiently blocked the ROS-inflammation cycle by ROS scavenging and TLR4 inhibition. Benefited by the abundant noncovalent interactions of π-π stacking and hydrogen bonding between EGCG and Rh-gel, the co-assembled hydrogel had good mechanical strength and injectable property. Following the injection EGCG@Rh-gel into the damaged region of the mice's heart after I/R, the hydrogel enabled to achieve long-term sustained release and treatment, improve cardiac function, and significantly reduce the formation of scarring. Further studies demonstrated that these beneficial outcomes arise from the reduction of ROS production, inhibition of inflammation, and induction of anti-apoptosis in cardiomyocytes. Therefore, EGCG@Rh-gel is a promising drug delivery system to block the ROS-inflammation cycle for resisting myocardial I/R injury. STATEMENT OF SIGNIFICANCE: 1. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS effects for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS and inflammation. 2. ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. 3. Here, we designed an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and a rhein-peptide hydrogel (Rh-gel). EGCG@Rh-gel efficiently blocked the ROS-inflammation cycle by ROS scavenging and TLR4 inhibition. 4. EGCG@Rh-gel achieved long-term sustained release and treatment, improved cardiac function, and significantly reduced the formation of scarring after I/R. 5. The beneficial outcomes arise from reducing ROS production, inhibiting inflammation, and inducing anti-apoptosis in cardiomyocytes.
Assuntos
Catequina , Traumatismo por Reperfusão Miocárdica , Animais , Catequina/farmacologia , Cicatriz/tratamento farmacológico , Preparações de Ação Retardada/uso terapêutico , Hidrogéis/farmacologia , Hidrogéis/uso terapêutico , Inflamação/tratamento farmacológico , Camundongos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Espécies Reativas de Oxigênio , Receptor 4 Toll-LikeRESUMO
Although stem cell-derived exosomes have been recognized as new candidates for cell-free treatment in myocardial infarction (MI), the challenge to improve the exosome retention in ischemic tissue remains. Our previous research indicated that islet-1(ISL1) overexpression enhances the paracrine function of mesenchymal stem cells (MSCs) and promotes angiogenesis in a model of MI. In this study, genetically engineered ISL1-MSC-derived exosomes (ISL1-MSCs-Exo) were collected, and the contents were analyzed by exosomal RNA sequencing. Next, we investigated if ISL1-MSCs-Exo could exert therapeutic effects and their incorporation into a new angiogenin-1 hydrogel (Ang-1 gel) could boost the retention of exosomes and further enhance their protective effects. Our results demonstrated that ISL1-MSCs-Exo could play a therapeutic role in vitro and in vivo, which might be due to changed exosomal contents. Ang-1 gel increased the retention and enhanced the anti-apoptosis, proliferation, and angiogenic capacity of ISL1-MSCs-Exo in endothelial cells. Echocardiography revealed that Ang-1 gel significantly augment the therapeutic effects of ISL1-MSCs-Exo for MI. The main mechanism might result from increased retention of ISL1-MSCs-Exo, herein enhanced pro-angiogenetic effects in an ischemic heart. Taken together, our findings indicated that ISL1-MSCs-Exo had endothelium-protective and pro-angiogenic abilities alone and Ang-1 gel could notably retain ISL1-MSCs-Exo at ischemic sites, which improved the survival and angiogenesis of endothelial cells and accelerated the recovery of MI. These results not only shed light on the therapeutic mechanism of ISL1-MSCs-Exo incorporated with Ang-1 gel but also offer a promising therapeutic option for ischemic disease.
Assuntos
Exossomos , Células-Tronco Mesenquimais , Infarto do Miocárdio , Células Endoteliais/metabolismo , Exossomos/metabolismo , Humanos , Hidrogéis/metabolismo , Hidrogéis/farmacologia , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Neovascularização Patológica/metabolismo , Ribonuclease PancreáticoRESUMO
Long-term use of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) shows clinical benefits for rheumatoid arthritis (RA) treatment. However, there are growing concerns over the adverse effects of systemic drug administration. Therefore, a strategy that can enhance drug bioavailability while minimizing side effects is urgently needed, but remains a challenge in RA therapy. To this end, here we conjugated MTX with a supramolecular self-assembling hydrogel composed of d-amino acids with a sequence of GDFDFDY. It was shown that MTX-GDFDFDY hydrogels exhibited a favorable drug selectivity behavior that they increased MTX toxicity toward RA synoviocytes, but reduce toxicity toward normal cells. Moreover, MTX-GDFDFDY hydrogels not only effectively inhibited the proliferation and migration of RA synoviocytes, but also inhibited the polarization of proinflammatory M1 type macrophages to reduce inflammation. After intra-articularly injected the hydrogels into the joints of adjuvant induced arthritis (AIA) mice, we found that MTX-GDFDFDY hydrogels significantly alleviated RA syndromes of joint swelling and fever compared to L-configuration MTX-GFFY hydrogels and free MTX. Furthermore, MTX-GDFDFDY hydrogels successfully protected cartilage though inhibiting synovial invasion and inflammation without causing systematic side effects. Therefore, d-amino acids supramolecular hydrogels can serve as an efficient and safe drug delivery system, showing a promising potential to improve RA therapy.
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Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation and iron overload, which is different from other types of programmed cell death, including apoptosis, necroptosis, autophagy, and pyroptosis. Over the past years, emerging studies have shown a close relation between ferroptosis and various cardiovascular diseases such as atherosclerosis, acute myocardial infarction, ischemia/reperfusion injury, cardiomyopathy, and heart failure. Herein, we will review the contributions of ferroptosis to multiple cardiovascular diseases and the related targets. Further, we discuss the potential ferroptosis-targeting strategies for treating different cardiovascular diseases.
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The reconstruction of blood perfusion is a crucial therapeutic method to save and protect cardiac function after acute myocardial infarction (AMI). The activation of the hepatocyte growth factor precursor (pro-HGF) has a significant effect on promoting angiogenesis and antiapoptosis. The oxygen/glucose deprivation (OGD) caused by AMI could induce vascular adventitia fibroblasts to differentiate into myofibroblasts and secrete the pro-HGF. Meanwhile, the specific Met receptor of the hepatocyte growth factor (HGF) is upregulated in endothelial cells during AMI. However, the poor prognosis of AMI suggests that the pro-HGF is not effectively activated. Improving the activation efficiency of the pro-HGF may play a positive role in the treatment of AMI. Herein, we designed supramolecular nanofibers self-assembled by compound 1 (Comp.1, Nap-FFEG-IVGGYPWWMDV), which can strongly activate the pro-HGF and initiate HGF-Met signaling. Studies have proven that Comp.1 possesses a better ability to activate the pro-HGF to perform antiapoptosis and pro-angiogenesis. In vivo results have confirmed that the retention time of Comp.1 and its accumulation in the infarct area of the heart are promoted. Moreover, Comp.1 plays an effective role in promoting angiogenesis in the marginal area of AMI, reducing myocardial fibrosis, and protecting cardiac function. Herein, we will optimize the structure of bioactive peptides through supramolecular self-assembly and amplify their therapeutic effect by improving their efficiency, providing a new strategy for the therapy of AMI.