RESUMO
BACKGROUND: Marfan syndrome (MFS) is associated with TGF (transforming growth factor) ß-stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFß induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta. METHODS: We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in Fbn1C1041G/+ mice, an established murine model of MFS (mMFS). mMFS mice were crossed to an IL11-tagged EGFP (enhanced green fluorescent protein; Il11EGFP/+) reporter strain or to a strain deleted for the IL11 receptor (Il11ra1-/-). In therapeutic studies, mMFS were administered an X209 (neutralizing antibody against IL11RA [IL11 receptor subunit alpha]) or IgG for 20 weeks and imaged longitudinally. RESULTS: IL11 mRNA and protein were elevated in the aortas of mMFS mice, as compared to controls. mMFS mice crossed to Il11EGFP/+ mice had increased IL11 expression in VSMCs, notably in the aortic root and ascending aorta. As compared to the mMFS parental strain, double mutant mMFS:Il11ra1-/- mice had reduced aortic dilatation and exhibited lesser fibrosis, inflammation, elastin breaks, and VSMC loss, which was associated with reduced aortic COL1A1 (collagen type I alpha 1 chain), IL11, MMP2/9, and phospho-ERK expression. To explore therapeutic targeting of IL11 signaling in MFS, we administered either a neutralizing antibody against IL11RA (X209) or an IgG control. After 20 weeks of antibody administration, as compared to IgG, mMFS mice receiving X209 had reduced thoracic and abdominal aortic dilation as well as lesser fibrosis, inflammation, elastin breaks, and VSMC loss. By immunoblotting, X209 was shown to reduce aortic COL1A1, IL11, MMP2/9, and phospho-ERK expression. CONCLUSIONS: In MFS, IL11 is upregulated in aortic VSMCs to cause ERK-related thoracic aortic dilatation, inflammation, and fibrosis. Therapeutic inhibition of IL11, imminent in clinical trials, might be considered as a new approach in MFS.
Assuntos
Doenças da Aorta , Síndrome de Marfan , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/farmacologia , Aorta/metabolismo , Doenças da Aorta/patologia , Modelos Animais de Doenças , Elastina/metabolismo , Fibrose , Imunoglobulina G/metabolismo , Inflamação/metabolismo , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11 , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Músculo Liso Vascular/metabolismo , Receptores de Interleucina-11/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1ß, and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Hepatócitos/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Necrose/metabolismoRESUMO
Repetitive pulmonary injury causes fibrosis and inflammation that underlies chronic lung diseases such as idiopathic pulmonary fibrosis (IPF). Interleukin 11 (IL11) is important for pulmonary fibroblast activation but the contribution of fibroblast-specific IL11 activity to lung fibro-inflammation is not known. To address this gap in knowledge, we generated mice with loxP-flanked Il11ra1 and deleted the IL11 receptor in adult fibroblasts (CKO mice). In the bleomycin (BLM) model of lung fibrosis, CKO mice had reduced fibrosis, lesser fibroblast ERK activation, and diminished immune cell STAT3 phosphorylation. Following BLM injury, acute inflammation in CKO mice was similar to controls but chronic immune infiltrates and pro-inflammatory gene activation, including NF-kB phosphorylation, were notably reduced. Therapeutic prevention of IL11 activity with neutralizing antibodies mirrored the effects of genetic deletion of Il11ra1 in fibroblasts. These data reveal a new function for IL11 in pro-inflammatory lung fibroblasts and highlight the important contribution of the stroma to inflammation in pulmonary disease.
Assuntos
Fibroblastos/metabolismo , Inflamação/metabolismo , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Bleomicina , Células Cultivadas , Doença Crônica , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Inflamação/genética , Interleucina-11/farmacologia , Subunidade alfa de Receptor de Interleucina-11/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , NF-kappa B/metabolismo , Fosforilação , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global posttranscriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. METHODS: Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these posttranscriptional mechanisms are also active in the diseased fibrotic human heart. RESULTS: We generated nucleotide-resolution translatome data during the transforming growth factor ß1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation, and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in posttranscriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same posttranscriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as Pumilio RNA binding family member 2 (PUM2) and Quaking (QKI) that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward profibrotic myofibroblasts in response to transforming growth factor ß1. CONCLUSIONS: We reveal widespread translational effects of transforming growth factor ß1 and define novel posttranscriptional regulatory networks that control the fibroblast-to-myofibroblast transition. These networks are active in human heart disease, and silencing of hub genes limits fibroblast activation. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.
Assuntos
Cardiopatias/genética , Cardiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Biossíntese de Proteínas/genética , Proteínas de Ligação a RNA/genética , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Perfilação da Expressão Gênica/métodos , Cardiopatias/patologia , Humanos , Análise de Sequência de RNA/métodos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays. RESULTS: HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.
Assuntos
Anticorpos Neutralizantes/farmacologia , Hepatite/prevenção & controle , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/antagonistas & inibidores , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Morte Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos , Células THP-1RESUMO
BACKGROUND AND PURPOSE: Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar damage and generally irreversible airflow limitation. Nuclear factor-κB (NF-κB) plays a critical role in COPD pathogenesis. Receptor-interacting protein 2 (Rip2), a 60 kDa adaptor protein, is a positive regulator of NF-κB pathway and also an inducible transcriptional product of NF-κB activation. We sought to investigate if Rip2 gene silencing could protect against cigarette smoke (CS)-induced acute lung injury. EXPERIMENTAL APPROACH: Gene silencing efficacy of Rip2 siRNA was characterized in mouse macrophage and mouse lung epithelial cell lines, and in a CS-induced acute lung injury mouse model. Bronchoalveolar lavage (BAL) fluid cell counts, levels of pro-inflammatory and oxidative damage markers, lung section inflammatory and epithelium thickness scorings, and nuclear NF-κB translocation were measured. KEY RESULTS: CS was found to upregulate Rip2 level in mouse lungs. Rip2 siRNA was able to suppress Rip2 levels in both macrophage and lung epithelial cell lines and in mouse lungs, block CS extract (CSE)-induced mediator release by the cultured cells, and abate neutrophil counts in BAL fluid from CS-challenged mice. Rip2 siRNA suppressed CS-induced inflammatory and oxidative damage markers, and nuclear p65 accumulation and transcriptional activation in lung tissues. Besides, Rip2 siRNA was able to disrupt CSE-induced NF-κB activation in a NF-κB reporter gene assay. CONCLUSIONS AND IMPLICATIONS: Taken together, we report for the first time that Rip2 gene silencing ameliorated CS-induced acute lung injury probably via disruption of the NF-κB activity, postulating that Rip2 may be a novel therapeutic target for COPD.
Assuntos
Lesão Pulmonar Aguda/terapia , Nicotiana/efeitos adversos , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fumaça/efeitos adversos , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Feminino , Inativação Gênica , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Doença Pulmonar Obstrutiva Crônica , RNA Interferente Pequeno , Proteína Serina-Treonina Quinase 2 de Interação com ReceptorRESUMO
Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens oxidative stress and impairs autophagy, advancing COPD progression. Andrographolide is a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata which has been a traditional medicinal herb for respiratory diseases. As airway epithelial cells form the first interface to be exposed to cigarette smoke, this study aimed to explore the modulatory effects of andrographolide on oxidative stress and autophagy in human bronchial epithelial BEAS-2B cells exposed to cigarette smoke extract (CSE). CSE (2%) exposure increased autophagic markers p62 and LC3B-II levels in BEAS-2B cells. Andrographolide alone increased p62 and p-p62 (S349) but not LC3B-II in BEAS-2B cells. However, in the presence of CSE, andrographolide was able to simultaneously increase LC3B-II level and enhance antioxidant defense by decreasing oxidative stress and increasing total antioxidant capacity, through upregulation of nuclear Nrf2 via the p62-Nrf2 positive feedback loop. Using RFP-GFP-LC3B transfected BEAS-2B cells exposed to CSE, andrographolide was found to impair autophagosome fusion with lysosome, which may account for the moderate increase in activated caspase 3/7 and annexin V levels. Our findings revealed for the first time that andrographolide simultaneously upregulated antioxidant defense through the p62-Nrf2 loop and moderately induced apoptosis through impairment of autophagic flux in CSE-exposed bronchial epithelium. Andrographolide facilitated cigarette smoke-induced apoptosis may be a potential toxicological outcome or may protect against chronic inflammation and aberrant DNA repair. Validation of these in-vitro findings in an experimental COPD model by andrographolide is warranted.
Assuntos
Antioxidantes/metabolismo , Autofagia/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Diterpenos/farmacologia , Células Epiteliais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fumaça/efeitos adversos , Apoptose/efeitos dos fármacos , Brônquios/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Fumar/efeitos adversos , Nicotiana/efeitos adversos , Regulação para Cima/efeitos dos fármacosRESUMO
Inhaled oligonucleotide is an emerging therapeutic modality for various common respiratory diseases, including obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD) and restrictive airway diseases like idiopathic pulmonary fibrosis (IPF). The advantage of direct accessibility for oligonucleotide molecules to the lung target sites, bypassing systemic administration, makes this therapeutic approach promising with minimized potential systemic side effects. Asthma, COPD, and IPF are common chronic respiratory diseases, characterized by persistent airway inflammation and dysregulated tissue repair and remodeling, although each individual disease has its unique etiology. Corticosteroids have been widely prescribed for the treatment of asthma, COPD, and IPF. However, the effectiveness of corticosteroids as an anti-inflammatory drug is limited by steroid resistance in severe asthma, the majority of COPD cases, and pulmonary fibrosis. There is an urgent medical need to develop target-specific drugs for the treatment of these respiratory conditions. Oligonucleotide therapies, including antisense oligonucleotide (ASO), small interfering RNA (siRNA), and microRNA (miRNA) are now being evaluated both pre-clinically and clinically as potential therapeutics. The mechanisms of action of ASO and siRNA are highly target mRNA specific, ultimately leading to target protein knockdown. miRNA has both biomarker and therapeutic values, and its knockdown by a miRNA antagonist (antagomir) has a broader but potentially more non-specific biological outcome. This review will compile the current findings of oligonucleotide therapeutic targets, verified in various respiratory disease models and in clinical trials, and evaluate different chemical modification approaches to improve the stability and potency of oligonucleotides for the treatment of respiratory diseases.
Assuntos
Asma/tratamento farmacológico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/uso terapêuticoRESUMO
Piezoelectric, pyroelectric, and ferroelectric materials are considered unique biomedical materials due to their dielectric crystals and asymmetric centers that allow them to directly convert various primary forms of energy in the environment, such as sunlight, mechanical energy, and thermal energy, into secondary energy, such as electricity and chemical energy. These materials possess exceptional energy conversion ability and excellent catalytic properties, which have led to their widespread usage within biomedical fields. Numerous biomedical applications have demonstrated great potential with these materials, including disease treatment, biosensors, and tissue engineering. For example, piezoelectric materials are used to stimulate cell growth in bone regeneration, while pyroelectric materials are applied in skin cancer detection and imaging. Ferroelectric materials have even found use in neural implants that record and stimulate electrical activity in the brain. This paper reviews the relationship between ferroelectric, piezoelectric, and pyroelectric effects and the fundamental principles of different catalytic reactions. It also highlights the preparation methods of these three materials and the significant progress made in their biomedical applications. The review concludes by presenting key challenges and future prospects for efficient catalysts based on piezoelectric, pyroelectric, and ferroelectric nanomaterials for biomedical applications.
Assuntos
Materiais Biocompatíveis , Regeneração Óssea , Materiais Biocompatíveis/farmacologia , Encéfalo , Catálise , Proliferação de CélulasRESUMO
Studies have indicated that medium- to long-duration spaceflight may adversely affect astronauts' emotional and social functioning. Emotion modulation can significantly impact astronauts' well-being, performance, mission safety and success. However, with the increase in flight time, the potential alterations in emotional and social performance during spaceflight and their underlying mechanisms remain to be investigated, and targeted therapeutic and preventive interventions have yet to be identified. We evaluated the changes of emotional and social functions in mice with the extension of the time in simulated space complex environment (SSCE), and simultaneously monitored changes in brain tissue of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and inflammation-related factors. Furthermore, we assessed the regulatory role of repetitive transcranial magnetic stimulation (rTMS) in mood and socialization with the extension of the time in SSCE, as well as examining alterations of VEGF signaling in the medial prefrontal cortex (mPFC). Our findings revealed that mice exposed to SSCE for 7 days exhibited depressive-like behaviors, with these changes persisting throughout SSCE period. In addition, 14 days of rTMS treatment significantly ameliorated SSCE-induced emotional and social dysfunction, potentially through modulation of the level of VEGF signaling in mPFC. These results indicates that emotional and social disorders increase with the extension of SSCE time, and rTMS can improve the performance, which may be related to VEGF signaling. This study offers insights into potential pattern of change over time for mental health issues in astronauts. Further analysis revealed that rTMS modulates emotional and social dysfunction during SSCE exposure, with its mechanism potentially being associated with VEGF signaling.
Assuntos
Depressão , Camundongos Endogâmicos C57BL , Transdução de Sinais , Comportamento Social , Voo Espacial , Estimulação Magnética Transcraniana , Fator A de Crescimento do Endotélio Vascular , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos , Masculino , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal/metabolismo , Metaloproteinase 9 da Matriz/metabolismoRESUMO
Microplastics (MPs) have emerged as a novel and highly concerning contaminant that is ubiquitous in the aqueous environment. However, the aging of MPs induced by dissolved organic matter (DOM), especially biochar-derived dissolved organic matter (BDOM), and the biological toxicity after aging are not fully understood. In this study, the effects of biochar-derived BDOMs on the photoaging and biotoxicity of MPs were investigated at different pyrolysis temperatures using micro-scale polyethylene (PE) as an example. The results showed that the amount of ·OH generated by the BDOM/PE systems was related to the molecular composition and structure of BDOMs. High temperature BDOM7/9 with less lignin-like (34.33 % / 41.80 %) and more lipid (24.58 % / 19.88 %) content could produce more ·OH by itself, and its binding ability with PE was weaker due to its less hydrophobic components (SUVA260 = 0.10 / 0.11), which resulted in a weaker shading effect and less inhibition of the system, thus resulting in more ·OH production in the high temperature BDOM7/9/PE system. However, the involvement of BDOM, although favoring the long-term stable ·OH production of the system, did not significantly promote the photoaging of MPs. Furthermore, combined in vivo and in vitro biotoxicity studies of MPs showed that photoaging PE with the involvement of BDOM greatly improved systemic inflammation and tissue damage, as well as reactive oxygen species (ROS, such as ·OH and -OH)-induced cell death. For example, the addition of BDOM5/PE-light reduced the cell death of human lung, liver, and kidney cells from 54.70 %, 69.39 %, and 48.35 % to 22.78 %, 33.13 %, and 25.83 %, respectively, compared to the PE-light group. The results of this study contribute to an in-depth understanding of the environmental behavior of BDOM and MPs systems.
Assuntos
Carvão Vegetal , Matéria Orgânica Dissolvida , Microplásticos , Humanos , Microplásticos/toxicidade , Plásticos , Temperatura , Pirólise , Polietileno , EnvelhecimentoRESUMO
Chronic diabetic wounds are at lifelong risk of developing diabetic foot ulcers owing to severe hypoxia, excessive reactive oxygen species (ROS), a complex inflammatory microenvironment, and the potential for bacterial infection. Here we develop a programmed treatment strategy employing live Haematococcus (HEA). By modulating light intensity, HEA can be programmed to perform a variety of functions, such as antibacterial activity, oxygen supply, ROS scavenging, and immune regulation, suggesting its potential for use in programmed therapy. Under high light intensity (658 nm, 0.5 W/cm2), green HEA (GHEA) with efficient photothermal conversion mediate wound surface disinfection. By decreasing the light intensity (658 nm, 0.1 W/cm2), the photosynthetic system of GHEA can continuously produce oxygen, effectively resolving the problems of hypoxia and promoting vascular regeneration. Continuous light irradiation induces astaxanthin (AST) accumulation in HEA cells, resulting in a gradual transformation from a green to red hue (RHEA). RHEA effectively scavenges excess ROS, enhances the expression of intracellular antioxidant enzymes, and directs polarization to M2 macrophages by secreting AST vesicles via exosomes. The living HEA hydrogel can sterilize and enhance cell proliferation and migration and promote neoangiogenesis, which could improve infected diabetic wound healing in female mice.
Assuntos
Diabetes Mellitus , Pé Diabético , Microalgas , Feminino , Animais , Camundongos , Espécies Reativas de Oxigênio , Antibacterianos/farmacologia , Hipóxia , Oxigênio , Cicatrização , HidrogéisRESUMO
Acute respiratory distress syndrome (ARDS) refers to acute diffuse lung injury caused by a variety of intrapulmonary and/or extrapulmonary factors such as infection and trauma. Uncontrolled inflammatory response is the main pathological feature. Different functional states of alveolar macrophages have different effects on inflammatory response. Transcription activating factor 3 (ATF3) is a fast response gene in the early stage of stress. In recent years, it has been found that ATF3 plays an important role in regulating the inflammatory response of ARDS by regulating the function of macrophages. This paper reviews the regulatory effects of ATF3 on alveolar macrophage polarization, autophagy and endoplasmic reticulum stress and its effects on the inflammatory process of ARDS, aiming to provide a new research direction for the prevention and treatment of ARDS.
Assuntos
Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Humanos , Autofagia , Macrófagos , Macrófagos Alveolares , Fator 3 Ativador da Transcrição/metabolismoRESUMO
The advent of immunotherapy has marked a new era in cancer treatment, offering significant clinical benefits. Cell membrane as drug delivery materials has played a crucial role in enhancing cancer therapy because of their inherent biocompatibility and negligible immunogenicity. Different cell membranes are prepared into cell membrane nanovesicles (CMNs), but CMNs have limitations such as inefficient targeting ability, low efficacy, and unpredictable side effects. Genetic engineering has deepened the critical role of CMNs in cancer immunotherapy, enabling genetically engineered-CMN (GCMN)-based therapeutics. To date, CMNs that are surface modified by various functional proteins have been developed through genetic engineering. Herein, a brief overview of surface engineering strategies for CMNs and the features of various membrane sources is discussed, followed by a description of GCMN preparation methods. The application of GCMNs in cancer immunotherapy directed at different immune targets is addressed as are the challenges and prospects of GCMNs in clinical translation.
Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias , Imunoterapia , Membrana Celular/genética , Engenharia Genética , Neoplasias/terapiaRESUMO
As an indispensable strategy for tumor treatment, surgery may cause two major challenges: tumor recurrence and wound infection. Here, a thermoelectric therapeutic strategy is provided as either an independent cancer therapy or surgical adjuvant treatment. Bi0.5 Sb1.5 Te3 (BST) and Bi2 Te2.8 Se0.2 (BTS) nanoplates composed of Z-scheme thermoelectric heterojunction (BST/BTS) are fabricated via a two-step hydrothermal processes. The contact between BST and BTS constructs an interfacial electric field due to Fermi energy level rearrangement, guiding electrons in the conductive band (CB) of BTS combine with the holes in the valance band (VB) of BST, leaving stronger reduction/oxidation potentials of electrons and holes in the CB of BST and the VB of BTS. Moreover, under a mild temperature gradient, another self-built-in electric field is formed facilitating the migration of electrons and holes to their surfaces. Based on the PEGylated BST/BTS heterojunction, a novel thermoelectric therapy platform is developed through intravenous injection of BST/BTS and external cooling of the tumors. This thermoelectric strategy is also proved effective for combination cancer therapy with ß-elemene. Moreover, the combination of heterojunction and hydrogel is administrated on the wound after surgery, achieving efficient residual tumor treatment and antibacterial effects.
Assuntos
Neoplasias , Sesquiterpenos , Adjuvantes Imunológicos , Terapia Combinada , AntibacterianosRESUMO
Photocatalytic oxidation technology holds promise for ideal advanced treatment of antibiotic wastewater. Single-atom catalysts (SACs) are a new hotspot in catalytic science, but the photochemical studies on the removal of antibiotics from water and biocompatibility after entering the environment are scarce. In this work, we prepared a single Mn atom immobilized on N-doped biochar (Mn@N-Biochar) by impregnation calcination method for enhancing photocatalytic degradation of sulfanilamide (SNM) in different types of various water systems. Compared with the original biochar, Mn@N-Biochar showed enhanced SNM degradation and TOC removal capacity. DFT calculation concluded that the electrons of d-orbital (Mn) and p-orbital (N) altered the electronic structure of biochar and enhanced the photoelectric performance. It was shown that Mn@N-Biochar caused negligible systemic inflammation and tissue damage when given orally in mice, and also did not alter cell death and ROS production in human lung, kidney, and liver cells, as compared with biochar. We are convinced that Mn@N-Biochar could enhance the photocatalytic degradation of antibiotics while maintaining biocompatibility, which could be a promising strategy for wastewater treatment.
Assuntos
Antibacterianos , Elétrons , Humanos , Animais , Camundongos , Antibacterianos/farmacologia , Sulfanilamida , Carvão Vegetal/farmacologia , Carvão Vegetal/química , ÁguaRESUMO
The exogenous excitation requirement and electron-hole recombination are the key elements limiting the application of catalytic therapies. Here a tumor microenvironment (TME)-specific self-triggered thermoelectric nanoheterojunction (Bi0.5Sb1.5Te3/CaO2 nanosheets, BST/CaO2 NSs) with self-built-in electric field facilitated charge separation is fabricated. Upon exposure to TME, the CaO2 coating undergoes rapid hydrolysis, releasing Ca2+, H2O2, and heat. The resulting temperature difference on the BST NSs initiates a thermoelectric effect, driving reactive oxygen species production. H2O2 not only serves as a substrate supplement for ROS generation but also dysregulates Ca2+ channels, preventing Ca2+ efflux. This further exacerbates calcium overload-mediated therapy. Additionally, Ca2+ promotes DC maturation and tumor antigen presentation, facilitating immunotherapy. It is worth noting that the CaO2 NP coating hydrolyzes very slowly in normal cells, releasing Ca2+ and O2 without causing any adverse effects. Tumor-specific self-triggered thermoelectric nanoheterojunction combined catalytic therapy, ion interference therapy, and immunotherapy exhibit excellent antitumor performance in female mice.
Assuntos
Peróxido de Hidrogênio , Neoplasias , Feminino , Animais , Camundongos , Imunoterapia , Neoplasias/terapia , Apresentação de Antígeno , Transporte Biológico , Microambiente TumoralRESUMO
Fenton reaction-based chemodynamic therapy is hardly a self-sufficient cancer treatment, due to its stringent reaction conditions, limited substrate concentration, and negative feedback from the tumor microenvironment. Herein, we synthesized a novel two-dimensional (2D) vanadium-based nanosheets (Vanadene, V NSs) with polyvalent surfaces (VIV/VV), a very narrow band gap of 0.8 eV, and high biodegradability by a liquid-phase exfoliation strategy. The polyvalent surface endowed its multiple capabilities to modulate TME through GSH consumption and O2 production via VV and to catalyze a Fenton-like reaction to produce ·OH under a mild condition via VIV. In addition, efficient energy conversions including near-infrared (NIR)-thermal conversion (photothermal therapy, PTT) and NIR-electron conversion (photodynamic therapy, PDT) were ensured by the narrow band gap, in which NIR-thermal conversion enhanced the Fenton-like reaction activity through accelerating ionization while NIR-electron conversion catalyzed the conversion of O2 to ·O2- for further breaking redox homeostasis. Moreover, V NSs-based nanocatalyst can be slowly degraded into non-toxic species, enabling it to be innocuously eliminated from the body after completing tumor eradication by single drug injection and single NIR irradiation. Therefore, this study provides new insights into a universal nanoplatform for NIR-enhanced combination cancer therapy, highlighting the utility of 2D V NSs in the field of biomedicine.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Catálise , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fototerapia/métodos , Microambiente Tumoral , VanádioRESUMO
Hydrogels have blossomed as superstars in various fields, owing to their prospective applications in tissue engineering, soft electronics and sensors, flexible energy storage, and biomedicines. Two-dimensional (2D) nanomaterials, especially 2D mono-elemental nanosheets (Xenes) exhibit high aspect ratio morphology, good biocompatibility, metallic conductivity, and tunable electrochemical properties. These fascinating characteristics endow numerous tunable application-specific properties for the construction of Xene-based hydrogels. Hierarchical multifunctional hydrogels can be prepared according to the application requirements and can be effectively tuned by different stimulation to complete specific tasks in a spatiotemporal sequence. In this review, the synthesis mechanism, properties, and emerging applications of Xene hydrogels are summarized, followed by a discussion on expanding the performance and application range of both hydrogels and Xenes.
RESUMO
High mobility group protein B1 (HMGB1), a highly conversed non-histone nucleoproteins with strong pro-inflammatory property, is one of the inflammatory mediator of the acute respiratory distress syndrome (ARDS). Numerous studies have confirmed that HMGB1 regulates ARDS by binding to receptor for advanced glycation end product (RAGE), Toll-like receptor (TLR) and etc. And it can significantly increase the mortality of ARDS. But the mechanism of HMGB1 release is still unclear. This study focuses on the HMGB1 release progress, which connected with Janus kinases/signal transducer and activator of transcription (JAK/STAT), nuclear factor-κB (NF-κB), Notch, inflammasome, tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS), peroxisome proliferator-activated receptor (PPAR) and other signaling or dependent pathways in ARDS.