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Effectively eliminating apoptotic cells is precisely controlled by a variety of signaling molecules and a phagocytic effect known as efferocytosis. Abnormalities in efferocytosis may bring about the development of chronic conditions, including angiocardiopathy, chronic inflammatory diseases and autoimmune diseases. During wound healing, failure of efferocytosis leads to the collection of apoptosis, the release of necrotic material and chronic wounds that are difficult to heal. In addition to the traditional phagocytes-macrophages, other important cell species including dendritic cells, neutrophils, vascular endothelial cells, fibroblasts and keratinocytes contribute to wounding healing. This review summarizes how efferocytosis-mediated immunomodulation plays a repair-promoting role in wound healing, providing new insights for patients suffering from various cutaneous wounds.
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OBJECTIVE: Hypoglossal-facial nerve anastomosis (HFA) is the most commonly used surgical treatment for severe facial palsy that does not respond to conservative treatments. A major complication of HFA is the loss of tongue function. The authors aimed to evaluate whether anastomosing the transected hypoglossal nerve using the ramus descendens hypoglossi could prevent tongue deviation and dysfunction in patients undergoing HFA. METHODS: In this randomized trial, adult patients with severe peripheral facial palsy (House-Brackmann grade V or VI) who did not respond to at least 6 months of conservative treatment were randomized at a 1:1 ratio to undergo either HFA alone (control group) or HFA plus anastomosis between the hypoglossal nerve and descendens hypoglossi (intervention group). The primary endpoint was tongue deviation angle at 12 months. Key secondary endpoints included tongue disability (chewing difficulty, swallowing defect, and articulation defect), tongue disability index (TDI; range 1-4, with a higher score indicating more severe disability), and facial nerve function. RESULTS: Twenty patients were enrolled (10 in each group). At 12 months, the tongue deviation angle was significantly lower in the intervention group than in the control group (7.8° ± 5.1° vs 23.6° ± 9.6°, p < 0.001). Although not statistically significant, the intervention group had lower rates of chewing difficulty (1/10 vs 3/10, p = 0.58), swallowing defect (1/10 vs 5/10, p = 0.14), and articulation defect (2/10 vs 6/10, p = 0.17). TDI was significantly lower in the intervention group (1.5 ± 0.6 vs 2.5 ± 0.3, p < 0.001). The percentage of the patients achieving House-Brackmann grade II or III was 80% in each group. CONCLUSIONS: Anastomosis of the descendens hypoglossi to the transected hypoglossal nerve attenuated tongue deviation in patients undergoing HFA for facial palsy, without compromising facial nerve function. Clinical trial registration no: ChiCTR2000034372 (Chinese Clinical Trials Registry).
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Doxorubicin (Dox), an anthracycline antibiotic, is widely used in cancer treatment. Although its antitumor efficacy appears significant, its clinical use is greatly restricted by its induction of cardiotoxicity. Cardiac senescence drives the Dox-induced cardiotoxicity, but whether diminishing these senescent cardiomyocytes could alleviate the cardiotoxicity remains unclear. Here, we assessed whether senescent cardiomyocytes have a senescence-associated secretory phenotype (SASP) that affects healthy non-senescent cardiomyocytes, rendering them senescent via the delivery of exosomes. Additionally, we explored whether targeting SASP senescent cardiomyocytes using a Bcl-2 inhibitor could alleviate cardiotoxicity. Cardiac damage was induced in a mouse model of continuous Dox treatment in vivo, and cardiomyocytes in vitro. Immunofluorescence of the senescence markers of Cdkn2a, Cdkn1a and γ-H2A.X was used to assess the SASP in the Dox-treated heart. To explore the molecular mechanisms involved, the Bcl-2 inhibitor ABT-199 was employed to eliminate SASP senescent cardiomyocytes. We show that the cardiomyocytes acquire a SASP during Dox treatment. The senescent cardiomyocytes upregulated Bcl-2, although treatment of mice with ABT-199 selectively eliminated SASP senescent cardiomyocytes involved in Dox-induced cardiotoxicity, thus leading to partial alleviation of Dox-induced cardiotoxicity. Moreover, we concluded that SASP factors secreted by senescent cardiomyocytes induced by Dox renders otherwise healthy cardiomyocytes senescent through exosome delivery. Our findings suggest that SASP senescent cardiomyocytes are a significant component of the pathogenesis of Dox-dependent cardiotoxicity and indicate that targeting the clearance of SASP senescent cardiomyocytes could be a new therapeutic approach for Dox-induced cardiac injury.
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The global increase of cutaneous wounds imposes huge health and financial burdens on patients and society. Despite improved wound healing outcomes, conventional wound dressings are far from ideal, owing to the complex healing process. Smart wound dressings, which are sensitive to or interact with changes in wound condition or environment, have been proposed as appealing therapeutic platforms to effectively facilitate wound healing. In this review, the wound healing processes and features of existing biomaterials are firstly introduced, followed by summarizing the mechanisms of smart responsive materials. Afterwards, recent advances and designs in smart and versatile materials of extensive applications for cutaneous wound healing were submarined. Finally, clinical progresses, challenges and future perspectives of the smart wound dressing are discussed. Overall, by mapping the composition and intrinsic structure of smart responsive materials to their individual needs of cutaneous wounds, with particular attention to the responsive mechanisms, this review is promising to advance further progress in designing smart responsive materials for wounds and drive clinical translation.
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BACKGROUND: Impaired wound re-epithelialization contributes to cutaneous barrier reconstruction dysfunction. Recently, N6-methyladenosine (m6A) RNA modification has been shown to participate in the determination of RNA fate, and its aberration triggers the pathogenesis of numerous diseases. Howbeit, the function of m6A in wound re-epithelialization remains enigmatic. METHODS: Alkbh5â/â mouse was constructed to study the rate of wound re-epithelialization after ALKBH5 ablation. Integrated high-throughput analysis combining methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq was used to identify the downstream target of ALKBH5. In vitro and in vivo rescue experiments were conducted to verify the role of the downstream target on the functional phenotype of ALKBH5-deficient cells or animals. Furthermore, the interacting reader protein and regulatory mechanisms were determined through RIP-qPCR, RNA pull-down, and RNA stability assays. RESULTS: ALKBH5 was specifically upregulated in the wound edge epidermis. Ablation of ALKBH5 suppressed keratinocyte migration and resulted in delayed wound re-epithelialization in Alkbh5â/â mouse. Integrated high-throughput analysis revealed that PELI2, an E3 ubiquitin protein ligase, serves as the downstream target of ALKBH5. Concordantly, exogenous PELI2 supplementation partially rescued keratinocyte migration and accelerated re-epithelialization in ALKBH5-deficient cells, both in vitro and in vivo. In terms of its mechanism, ALKBH5 promoted PELI2 expression by removing the m6A modification from PELI2 mRNA and enhancing its stability in a YTHDF2-dependent manner. CONCLUSIONS: This study identifies ALKBH5 as an endogenous accelerator of wound re-epithelialization, thereby benefiting the development of a reprogrammed m6A targeted therapy for refractory wounds.
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Chronic non-healing wounds, a prevalent complication of diabetes, are associated with increased mortality in diabetic patients. Excessive accumulation of M1 macrophages in diabetic wounds promotes inflammation and results in dysregulated tissue repair. Adipose tissue macrophages (ATMs) derived from healthy lean donors have the ability to improve glucose tolerance and insulin sensitivity, as well as modulate inflammation. MicroRNAs (miRs), which can be packaged into exosomes (Exos) and secreted from cells, serve as essential regulators of macrophage polarization. Here, we revealed that ATMs isolated from lean mice secrete miRs-containing Exos, which modulate macrophage polarization and promote rapid diabetic wound healing when administered to diabetes-prone db/db mice. The miRs sequence of tissue samples from wounds treated with Exos secreted by lean ATMs (ExosLean) revealed that miR-222-3p was up-regulated. Further analyses showed that inhibiting miR-222-3p using a miR inhibitor impaired the macrophage-reprogramming effect of ExosLean. In the excisional skin wound mouse model, locally inhibiting miR-222-3p disrupted healing dynamics and failed to modulate macrophage polarization. Mechanistic studies revealed a connection between miR-222-3p, Bcl2l11/Bim, an inflammatory response effector, macrophage polarization, and diabetic wound healing. In summary, ExosLean act as positive regulators of macrophage polarization by regulating miR levels in wounds and accelerating wound healing, and thus have important implications for wound management in diabetes.
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Diabetes Mellitus , Exosomas , MicroARNs , Ratones , Animales , Tejido Adiposo , MicroARNs/genética , MicroARNs/farmacología , Inflamación , Macrófagos , Cicatrización de HeridasRESUMEN
Ammonia (NH3) and nitrous oxide (N2O) have been regarded as the typical secondary pollutants emitted from vehicles equipped with a three-way catalyst (TWC). MultiGas FT-IR Analyzer was applied to determine the outlet gas concentrations in the light-off experiments, in order to understand how different reaction conditions and catalyst aging affect the production of these two pollutants. It was found that N2O formation is favored by the existence of excess oxygen during NO reduction, whereas NH3 is readily formed within the lack of reactive oxygen species. Interestingly, the reduction of NO by H2 in presence of excess oxygen can also lead to NH3 formation when the active metal particles are large enough, which provides the rational explanation why the increased NH3 was emitted from older gasoline vehicles. The loss of the catalytically active sites and reducibility caused by thermal aging requires longer time to warm-up thereby favors the N2O and NH3 formation, which is the major reason for the higher CO, NOx, HC, N2O and NH3 emissions from the old gasoline vehicles than that of low-mileage gasoline vehicles.
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Contaminantes Atmosféricos , Amoníaco , Contaminantes Atmosféricos/análisis , Amoníaco/análisis , Catálisis , Gasolina , Óxido Nitroso , Oxígeno , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Aged skin wounds heal poorly, resulting in medical, economic, and social burdens posed by nonhealing wounds. Age-related defects in repair are associated with reduced myofibroblasts and dysfunctional extracellular matrix (ECM) deposition. Bidirectional cell-cell communication involving exosome-borne cargo such as micro RNAs (miRs) has emerged as a critical mechanism for wound healing and aged tissue regeneration. Here we report that at the wound edge, aged fibroblasts display reduced migration and differentiation into myofibroblasts, with impaired ECM deposition, when compared with young tissue. Proper activation of fibroblasts to myofibroblasts may alleviate age-related defects in wound healing. Herein, an exosome-guided cell technique was performed to induce effective wound healing. Supplementing wounds with exosomes isolated from young mouse wound-edge fibroblasts (exosomesYoung) significantly improved the abundance of myofibroblasts and wound healing in aged mice and caused fibroblasts to migrate and transition to myofibroblasts in vitro. To determine the underlying mechanism, we found that exosomal transfer of miR-125b to fibroblasts inhibited sirtuin 7 (Sirt7), thus accelerating myofibroblast differentiation and wound healing in aged mice. Notably, after epidermal inhibition of miR-125b or overexpression of Sirt7 in fibroblasts, migration and myofibroblast transition were perturbed. Our findings thus reveal that miR-125b is transferred through exosomes from young fibroblasts to old fibroblasts contributes to promoting fibroblast migration and transition to counteract aging, suggesting a potential avenue for anti-aging interventions in wound healing.
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Exosomas , MicroARNs , Animales , Diferenciación Celular , Fibroblastos , Ratones , MicroARNs/genética , Cicatrización de HeridasRESUMEN
Doxorubicin (Dox), an important anthracycline, is a potent anticancer agent that is used for treating solid tumors and hematologic malignancies. However, its clinical use is hampered by cardiac cardiotoxicity. This study aimed to investigate the cardioprotective potential of miR-199a-3p. Continuous Dox treatment not only markedly induced cardiomyocyte senescence but also resulted in a growing number of senescence-associated secretory phenotype (SASP) cardiomyocytes, frequently leading to heart senescence. This study showed that miR-199a-3p was downregulated in cardiomyocytes when exposed to Dox. The cardiac-specific overexpression of miR-199a-3p promoted cell cycle re-entry and cell proliferation, resulting in relief from cardiac senescence. Also, the elevation of miR-199a-3p inhibited the generation of SASP, thus, hampering the spread of senescence. In cardiomyocytes, the modulation of miR-199a-3p changed the levels of senescence-related protein GATA4. The ectopic expression of GATA4 blunted the anti-senescence effect of miR-199a-3p. Together, the data supported a role for miR-199a-3p during Dox cardiotoxicity. The elevation of miR-199a-3p might provide a dual therapeutic advantage in Dox cardiotoxicity therapy by simultaneously preventing cardiac senescence and reducing the spread of senescence.
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Envejecimiento/efectos de los fármacos , Antibióticos Antineoplásicos/toxicidad , Cardiotoxicidad/tratamiento farmacológico , Doxorrubicina/toxicidad , MicroARNs/uso terapéutico , Comunicación Paracrina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Cardiotoxicidad/etiología , Proliferación Celular/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. However, its high cardiotoxicity hampered its clinical use. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosomeMIF in the treatment of DIC. RESULTS: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF). Regulatory lncRNAs activated by MIF pretreatment were explored using genomics approaches. Fluorescence-labeled exosomes were tracked in vitro by fluorescence imaging. In vivo and in vitro, miR-221-3p mimic transfection enforced miR-221-3p overexpression, and senescence-associated ß-galactosidase assay was applied to test cellular senescence. Exosomal delivering LncRNA-NEAT1 induced therapeutic effect in vivo was confirmed by echocardiography. It demonstrated that exosomesMIF recovered the cardiac function and exerted the anti-senescent effect through LncRNA-NEAT1 transfer against Dox. TargetScan and luciferase assay showed that miR-221-3p targeted the Sirt2 3'-untranslated region. Silencing LncRNA-NEAT1 in MSCs, miR-221-3p overexpression or Sirt2 silencing in cardiomyocytes decreased the exosomeMIF-induced anti-senescent effect against Dox. CONCLUSIONS: The results indicated exosomeMIF serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA-NEAT1 transfer, thus inhibiting miR-221-3p and leading to Sirt2 activation. The study proposed that exosomeMIF might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy.
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Cardiotoxicidad/prevención & control , Doxorrubicina/efectos adversos , Exosomas/química , Oxidorreductasas Intramoleculares/química , Factores Inhibidores de la Migración de Macrófagos/química , Células Madre Mesenquimatosas/química , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Doxorrubicina/farmacología , Regulación de la Expresión Génica , Lesiones Cardíacas/inducido químicamente , Lesiones Cardíacas/genética , Lesiones Cardíacas/prevención & control , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Miocitos Cardíacos/efectos de los fármacos , Transducción de Señal , Sirtuina 2/metabolismoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have been an important therapeutic advancement in the field of cancer medicine. Recent reports provided greater insights into the cardiovascular adverse events, which prohibited the use of ICIs. Cardiovascular adverse events occur in different forms, such as myocarditis and cardiomyopathy, myocardial fibrosis, heart failure and pericardial disease. Cardiac aging overlapped with the occurrence of some cardiac diseases. Exosomes mediate cell-cell cross talk in cardiac diseases by transferring a variety of biomolecules, including microRNAs (miRs). miR-34a-5p is a well-known miR associated with the cardiac senescence. This study aimed to investigate whether cardiovascular adverse effects of the programmed cell death 1 (PD-1) inhibitor, a widely used ICI, were related to exosomal-transferred miR-34a-5p in cardiac senescence in a mouse model. METHODS AND RESULTS: The upregulation of miR-34a-5p in cardiomyocytes induced by exosomes derived from PD-1 inhibitor-treated macrophages, accompanied by cardiac senescence, caused cardiac injury in mouse hearts. miR-34a-5p was identified as an exosomal transfer RNA to induce cardiac senescence-related injury. Inhibiting miR-34a-5p in macrophages attenuated the exosomePD-1 inhibitor-induced pro-senescent effect in cardiomyocytes. TargetScan and luciferase assay showed that miR-34a-5p targeted the serine/threonine-protein phosphatase 1 regulatory subunit 10 (PNUTS) 3'-untranslated region. CONCLUSIONS: Exosomes derived from PD-1 inhibitor-treated macrophages exerted a pro-senescent effect by modulating the miR-34a-5p/PNUTS signaling pathway. The findings might supply new targets to ameliorate cardiac injury in patients with cancer receiving PD-1 inhibitor treatment.
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Inhibidores de Puntos de Control Inmunológico/metabolismo , Macrófagos/metabolismo , MicroARNs/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , TransfecciónRESUMEN
An amendment to this paper has been published and can be accessed via the original article.
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Many factors are involved in the process of nerve regeneration. Understanding the mechanisms regarding how these factors promote an efficient remyelination is crucial to deciphering the molecular and cellular processes required to promote nerve repair. Schwann cells (SCs) play a central role in the process of peripheral nerve repair/regeneration. Using a model of facial nerve crush injury and repair, we identified Annexin A1 (ANXA1) as the extracellular trigger of SC proliferation and migration. ANXA1 activated formyl peptide receptor 2 (FPR2) receptors and the downstream adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling cascade, leading to SC proliferation and migration in vitro. SCs lacking FPR2 or AMPK displayed a defect in proliferation and migration. After facial nerve injury (FNI), ANXA1 promoted the proliferation of SCs and nerve regeneration in vivo. Collectively, these data identified the ANXA1/FPR2/AMPK axis as an important pathway in SC proliferation and migration. ANXA1-induced remyelination and SC proliferation promotes FNI regeneration.
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Anexina A1/metabolismo , Movimiento Celular , Proliferación Celular , Traumatismos del Nervio Facial/metabolismo , Regeneración Nerviosa , Células de Schwann/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Anexina A1/genética , Células Cultivadas , Masculino , Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Lipoxina/genética , Receptores de Lipoxina/metabolismo , Células de Schwann/fisiología , Transducción de SeñalRESUMEN
Cancer immunotherapy has become a well-established treatment option for some cancers; however, its use is hampered by its cardiovascular adverse effects. Immune checkpoint inhibitors (ICIs)-related cardiac toxicity took place in kinds of different forms, such as myocarditis, acute coronary syndrome, and pericardial disease, with high mortality rates. This study aimed to investigate the roles of programmed death-1 (PD-1) inhibitor, one of widespread used ICIs, in the development of murine cardiac injury. PD-1 inhibitor is known to transduce immunoregulatory signals that modulate macrophages polarization to attack tumor cells. Hence, this study explored whether the cardiovascular adverse effects of PD-1 inhibitor were related to macrophage polarization. MicroRNA-34a (miR-34a), which appears to regulate the polarization of cultured macrophages to induce inflammation, is examined in cardiac injury and macrophage polarization induced by the PD-1 inhibitor. As a target of miR-34a, Krüppel-like factor 4 (KLF4) acted as an anti-inflammation effector to take cardiac protective effect. Further, it investigated whether modulating the miR-34a/KLF4-signaling pathway could influence macrophage polarization. The PD-1 inhibitor markedly induced M1 phenotype macrophage polarization with impaired cardiac function, whereas miR-34a inhibitor transfection treatment reversed M1 polarization and cardiac injury in vivo. In vitro, PD-1 inhibitor-induced M1 polarization was accompanied by an increase in the expression of miR-34a but a decrease in the expression of KLF4. TargetScan and luciferase assay showed that miR-34a targeted the KLF4 3'-untranslated region. Either miR-34a inhibition or KLF4 overexpression could abolish M1 polarization induced by the PD-1 inhibitor. The findings strongly suggested that the PD-1 inhibitor exerted its effect in promoting M1 polarization and cardiac injury by modulating the miR-34a/KLF4-signaling pathway and inducing myocardial inflammation. These findings might help us to understand the pathogenesis of cardiac injury during immunotherapy, and provide new targets in ameliorating cardiac injury in patients with cancer receiving PD-1 inhibitor treatment.
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Polaridad Celular , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Factores de Transcripción de Tipo Kruppel/metabolismo , Macrófagos/patología , MicroARNs/metabolismo , Miocardio/patología , Transducción de Señal , Animales , Secuencia de Bases , Diferenciación Celular/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Pruebas de Función Cardíaca , Factor 4 Similar a Kruppel , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenotipo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.
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The clinical application of doxorubicin (Dox) is limited due to its undesirable cardiotoxicity side effects. Cellular senescence plays an important role in Dox-induced cardiotoxicity. Exosomes derived from stem cells showed a therapeutic effect in Dox-induced cardiomyopathy (DIC). Hypoxia-preconditioned exosomes (exosomeHypoxia) display pro-metabolism and pro-survival abilities. Several long-noncoding RNAs/microRNAs act as competing endogenous RNAs (ceRNAs) modulating DIC. No study investigated whether exosomeHypoxia could attenuate DIC through modulating ceRNAs.Treatment of the human adipose-derived mesenchymal stem cells with hypoxia induced lncRNA-MALAT1 accumulation in the secreted exosomes. In addition, the lncRNA-MALAT1 was identified as an exosomal transfer RNA to repress miR-92a-3p expression. Silencing the lncRNA-MALAT1 in MSCs or miR-92a-3p overexpression in cardiomyocytes significantly impaired the rejuvenation induced by exosomeHypoxia. TargetScan and luciferase assay showed that miR-92a-3p targeted the ATG4a 3' untranslated region. Silencing ATG4a blocked the anti-senescent effect of exosomeHypoxia.This study identified the lncRNA-MALAT1 that functioned as ceRNA binding to miR-92a-3p, leading to ATG4a activation, thus improving mitochondrial metabolism. LncRNA-MALAT1/miR-92a-3p/ATG4a partially mediates the cardioprotective roles of exosomeHypoxia in Dox-induced cardiac damage. ExosomeHypoxia may serve as a potential therapeutic target against DIC.
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Proteínas Relacionadas con la Autofagia/genética , Senescencia Celular/efectos de los fármacos , Cisteína Endopeptidasas/genética , Doxorrubicina/efectos adversos , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/genética , Regulación hacia Arriba , Apoptosis , Proteínas Relacionadas con la Autofagia/metabolismo , Cardiotoxicidad , Línea Celular , Cisteína Endopeptidasas/metabolismo , Exosomas/genética , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , ARN Largo no Codificante/metabolismoRESUMEN
Facial paralysis can result in severe implications for patients. A good prognosis depends on the degree of nerve regeneration. Schwann cells (SCs) play an important role in facial nerve development and regeneration through migration. Forkhead box C1 (Foxc1), a member of the forkhead transcription factor family, is implicated in cell migration. However, the role of Foxc1 in the progression after facial nerve crush remains unknown. Our aim was to evaluate the effect of Foxc1 overexpression on SC migration and recovery of facial nerves after crush injury. The rat facial nerve crush injury model was established through the use of unilateral surgery. The results showed that the expression of Foxc1 was increased in the surgery group compared to that of the control group. SCs were isolated from the sciatic nerves and cultured. Foxc1, delivered by an adeno-associated virus in vivo, or adenovirus in vitro, both induced overexpression of Foxc1, and increased the expression of CXCL12 and ß-catenin. After the transfection of Foxc1, the migration of SC was increased both in vitro and in vivo, was reduced by the inhibition of CXCL12 or ß-catenin. The facial nerve function and the nerve axon remyelination of the rats transfected with Foxc1 were significantly improved after nerve crush injury. Overall, the results demonstrated that overexpression of Foxc1 promoted SC migration by regulating CXCL12 via the Wnt/ß-catenin pathway, thus contributing to improved facial nerve function after crush injury.
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Traumatismos del Nervio Facial/terapia , Nervio Facial/cirugía , Factores de Transcripción Forkhead/genética , Regeneración Nerviosa/genética , Animales , Movimiento Celular/genética , Quimiocina CXCL12/genética , Nervio Facial/patología , Traumatismos del Nervio Facial/genética , Traumatismos del Nervio Facial/patología , Factores de Transcripción Forkhead/farmacología , Regulación de la Expresión Génica/genética , Humanos , Ratas , Células de Schwann/citología , Células de Schwann/metabolismo , Nervio Ciático/citología , Nervio Ciático/metabolismo , Vía de Señalización Wnt/genética , beta Catenina/genéticaRESUMEN
AIMS: Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIF-pretreated MSCs in cardiomyocytes and to explore the underlying mechanisms. METHODS AND RESULTS: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF), and delivered to cardiomyocytes subjected to H2O2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. ExosomeMIF protected cardiomyocytes from H2O2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosomeMIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosomeMIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosomeMIF inhibited H2O2-induced apoptosis through modulating oxidative stress. CONCLUSIONS: Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosomeMIF in protecting cardiomyocytes from apoptosis.
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Exosomas/metabolismo , Proteína Forkhead Box O1/metabolismo , Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Cardiotónicos/metabolismo , Cardiotónicos/farmacología , Proliferación Celular/fisiología , Humanos , Oxidorreductasas Intramoleculares/farmacología , Factores Inhibidores de la Migración de Macrófagos/farmacología , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Interferente Pequeño/metabolismo , Transducción de Señal , TransfecciónRESUMEN
The formation of ammonia (NH3) as a byproduct during the operation of a three-way catalyst (TWC) in a simulated exhaust stream was investigated using a commercially available Pd/Rh TWC under steady-state and lean/rich cycling conditions. Ion molecular reaction-mass spectrometry was applied to determine NO, NO2, and NH3 concentrations at a time resolution of 0.6 s. Catalyst aging was shown to result in a significant increase in the amount of NH3 formed, which has received limited attention in the literature to date. The selectivity toward NH3 formation has been shown to increase with the decrease in the oxygen storage capacity (OSC) of a TWC induced by thermal aging. NH3 has been shown to mainly form within the exhaust temperature range of 250-550 °C. Typical lambda and rich operational condition duration periods found in vehicle test procedures were also employed to investigate their effects on NH3 formation. The results suggest that a decrease in the lambda and/or an increase in the duration of rich operating conditions will lead to an increase in the selectivity toward NH3 formation. Improving the OSC of TWCs and effectively controlling the lambda near to 1.0 with limited duration in rich operating conditions are therefore significant factors in the reduction of NH3 emissions.