RESUMO
Spinal cord injury (SCI) is a devastating traumatic disease seriously impairing the quality of life in patients. Expectations to allow the hopeless central nervous system to repair itself after injury are unfeasible. Developing new approaches to regenerate the central nervous system is still the priority. Exosomes derived from mesenchymal stem cells (MSC-Exo) have been proven to robustly quench the inflammatory response or oxidative stress and curb neuronal apoptosis and autophagy following SCI, which are the key processes to rescue damaged spinal cord neurons and restore their functions. Nonetheless, MSC-Exo in SCI received scant attention. In this review, we reviewed our previous work and other studies to summarize the roles of MSC-Exo in SCI and its underlying mechanisms. Furthermore, we also focus on the application of exosomes as drug carrier in SCI. In particular, it combs the advantages of exosomes as a drug carrier for SCI, imaging advantages, drug types, loading methods, etc., which provides the latest progress for exosomes in the treatment of SCI, especially drug carrier.
Assuntos
Portadores de Fármacos , Exossomos , Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/terapia , Humanos , Células-Tronco Mesenquimais/metabolismo , Animais , Apoptose , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
The incorporation of chemo/photothermal/photodynamic therapy in subcellular organelles such as mitochondria has attracted extensive attention recently. Here, we designed mitochondria-targeted hollow mesoporous silica nanoparticles (THMSNs) loaded biocompatible phase-change material L-menthol (LM) via a facile method. Meanwhile, antitumor drug doxorubicin (DOX) and near-infrared (NIR) dye indocyanine green (ICG) approved by FDA were simultaneously encapsulated into THMSNs, denoted as THMSNs@LMDI, which showed NIR radiation triggered capacity for cancer treatment. With the mitochondria-targeted ability of triphenylphosphine, the resulting THMSNs@LMDI showed evidently improved cellular internalization and specific accumulation in mitochondria. Under NIR irradiation, the versatile ICG would be bound to simultaneously produce photodynamic and photothermal therapy. Meanwhile, in view of the solid-liquid phase transition feature of gatekeeper LM, THMSNs@LMDI provided a platform for NIR-mediated temperature-responsive DOX release. As a matter of course, these smart subcellular organelle-THMSNs could serve as an effective drug delivery platform for site-specific on-demand chemo/photothermal/photodynamic therapy of cancer.
Assuntos
Raios Infravermelhos , Mitocôndrias/metabolismo , Nanopartículas/química , Dióxido de Silício/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Verde de Indocianina/química , Verde de Indocianina/metabolismo , Verde de Indocianina/farmacologia , Mentol/química , Mentol/metabolismo , Mentol/farmacologia , Mitocôndrias/efeitos dos fármacos , Nanopartículas/toxicidade , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia , Fototerapia , Porosidade , Oxigênio Singlete/metabolismoRESUMO
The disturbance of podocyte motility is an essential pathogenic mechanisms of foot process effacement during proteinuric diseases, and myosin light chain (MLC) is a pivotal component in regulating the motility of podocytes. Inflammatory cytokine interleukin-6 (IL-6) has been reported to induce podocyte abnormalities by various mechanisms, however, whether aberrant cell motility contributes to the IL-6-induced podocyte injury remains unknown. Here, by wound healing, transwell, and cell migration assays, we confirmed that IL-6 accelerates the motility of podocyte. Simultaneously, the phosphorylation of MLC is elevated along with perturbed focal adhesion (FAs) and cytoskeleton. Next, via genetic and pharmacologic interruption of MLC or its phosphorylation we revealed that the activation of MLC is implicated in IL-6-mediated podocyte hypermotility as well as the disassembly of FAs and F-actin. By using stattic, an inhibitor for STAT3 phosphorylation, we uncovered that STAT3 activation is the upstream event for MLC phosphorylation and the following aberrant motility of podocytes. Additionally, we found that calcitriol markedly attenuates podocyte hypermotility via blocking STAT3-MLC. In conclusion, our study demonstrated that IL-6 interrupts FAs dynamic, cytoskeleton organization, and eventually leads to podocyte hypermotility via STAT3/MLC, whereas calcitriol exerts its protective role by inhibiting this pathway. These findings enrich the mechanisms accounting for IL-6-mediated podocyte injury from the standpoint of cell motility and provide a novel therapeutic target for podocyte disorders.
Assuntos
Movimento Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Adesões Focais/metabolismo , Interleucina-6/farmacologia , Cadeias Leves de Miosina/metabolismo , Podócitos/citologia , Podócitos/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Calcitriol/farmacologia , Citoesqueleto/efeitos dos fármacos , Adesões Focais/efeitos dos fármacos , Humanos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fibras de Estresse/efeitos dos fármacos , Fibras de Estresse/metabolismoRESUMO
The co-delivery of two or more anti-tumor agents using nanocarriers has shown great promise in cancer therapy, but more work is needed to selectively target drugs to specific subcellular organelles. To this end, our research has reported on "smart" polymeric nanoparticles that can encapsulate two different site-oriented pro-drug molecules, allowing them to reach their targeted subcellular organelles based on NIR-mediated controlled release, allowing for targeted modifications in the nucleus or the mitochondria. Specially, an all-trans retinoic acid (RA) conjugated cisplatin derivative (RA-Pt) can be delivered with high affinity to the nucleus of target cells, facilitating the binding of cisplatin to double-stranded DNA. Similarly, a synthesized derivative generated by conjugation of triphenylphosphine (TPP) and celastrol (TPP-Cet) may facilitate mitochondrial targeted drug delivery in tumor cells, inducing ROS accumulation and thereby leading to apoptosis. Relative to nanoparticles loaded with a single therapeutic agent, dual antitumor agent-loaded nanocarriers showed promising synergy, exhibiting significant tumor inhibition in vivo (81.5%), and less systemic toxicity than the free therapeutic agents alone or the drug-loaded nanoparticles without targeted ligands. These results indicated that site-oriented payloads can effectively enhance antitumor therapeutic efficiency and these studies offer a novel "multistage targeted-delivery" strategy in synergistic therapy for cancer treatment.
RESUMO
BACKGROUND/AIMS: Psychological complications are prevalent in patients with chronic kidney disease (CKD). This study aimed to investigate mental disorders in stage 4-5 CKD patients, to detect metabolite concentrations in the brain by proton magnetic resonance spectroscopy (1H-MRS) and to compare the effects of different dialysis therapies on mental disorders in end-stage renal disease (ESRD). METHODS: The sample population was made up of predialysis (13), hemodialysis (HD) (13), and peritoneal dialysis (PD) patients (12). We collected the baseline data of patients' age, sex, hemoglobin (Hb) and parathyroid hormoneï¼PTHï¼ levels. The predialysis patients served as the control group. The psychological status of the three groups was assessed using three psychological scales. 1H-MRS was used to evaluate the relative metabolite concentrations in the bilateral amygdala, hippocampus and unilateral anterior cingulated cortex (ACC). RESULTS: The psychological status was better in HD patients than in predialysis and PD patients. 1H-MRS alterations were predominantly found in the ACC. Choline-containing compounds relative to creatine (Cho/Cr), myo-inositol relative to creatine (MI/Cr) and glutamate and glutamine relative to creatine (Glx/Cr) in the ACC were higher in HD patients. 1H-MRS results were correlated with the baseline data and the scores of psychological scales. CONCLUSIONS: CKD patients showed different types of mental disorders as well as metabolite disturbances in the brain. The metabolite concentrations correlated with the psychological status which was better in HD than in predialytic and PD patients.
Assuntos
Transtornos Mentais/diagnóstico , Espectroscopia de Prótons por Ressonância Magnética/métodos , Insuficiência Renal Crônica/psicologia , Adulto , Idoso , Estudos de Casos e Controles , Giro do Cíngulo/metabolismo , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/psicologia , Transtornos Mentais/metabolismo , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal Crônica/metabolismoRESUMO
Murine double minute 2 (MDM2) is an E3-ubiquitin ligase critical for various biological functions. Previous data have revealed an indispensable role of MDM2 in kidney homeostasis. However, its role in glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation during hyperglycemia condition remains unclear. In our present study, we found that MDM2 protein level was significantly upregulated in high glucose-treated GMCs, while knocking down MDM2 by siRNA could attenuate high glucose-induced ECM accumulation and GMCs proliferation. Unexpectedly, Nutlin-3a, a MDM2-p53 interaction blocker, had no benefit in protecting diabetic mice from renal impairment in vivo and in alleviating high glucose-induced ECM accumulation in vitro. Intriguingly, we found that Notch1 signaling activation was obviously attenuated by MDM2 depletion in GMCs with high glucose exposure. However, Numb, a substrate of MDM2 which suppresses Notch1 signaling, was found not to be involved in the MDM2 and Notch1 association. Moreover, our findings demonstrated that MDM2 interacted with Notch1 intracellular domain (NICD1) independent of Numb and regulated the ubiquitination status of NICD1. Collectively, our data propose a pivotal role of MDM2 in high glucose-induced GMC proliferation and ECM accumulation, via modulating the activation of Notch1 signaling pathway in an ubiquitination-dependent way.
Assuntos
Glucose/administração & dosagem , Células Mesangiais/citologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Receptor Notch1/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glucose/farmacologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Camundongos , Ratos , Receptor Notch1/química , Transdução de Sinais , Ubiquitinação , Regulação para CimaRESUMO
It is well recognized that murine double minute gene 2 (MDM2) plays a critical role in cell proliferation and inflammatory processes during tumorigenesis. It is also reported that MDM2 is expressed in glomeruli and involved in podocyte injury. However, whether MDM2 is implicated in renal fibrosis remains unclear. Here we investigated the role of MDM2 in tubulointerstitial fibrosis (TIF). By immunohistochemical staining and Western blotting we confirmed that MDM2 is upregulated in the tubulointerstitial compartment in patients with TIF and unilateral urethral obstruction (UUO) mice, which mainly originates from myofibroblasts. Consistently, in vitro MDM2 is increased in TGF-ß1-treated fibroblasts, one of the major sources of collagen-producing myofibroblasts during TIF, along with fibroblast activation. Importantly, genetic deletion of MDM2 significantly attenuates fibroblast activation. We then analyzed the possible downstream signaling of MDM2 during fibroblast activation. p53-dependent pathway is the classic downstream signaling of MDM2, and Nutlin-3 is a small molecular inhibitor of MDM2-p53 interaction. To our surprise, Nutlin-3 could not ameliorate fibroblast activation in vitro and TIF in UUO mice. However, we found that Notch1 signaling is attenuated during fibroblast activation, which could be markedly rescued by MDM2 knockdown. Overexpression of intracellular domain of Notch1 (NICD) by plasmid could obviously minimize fibroblast activation induced by TGF-ß1. In addition, the degradation of NICD is strikingly suppressed by PYR-41, an inhibitor of ubiquitin-activating enzyme E1, and proteasome inhibitor MG132. Taken together, our findings provide the first evidence that MDM2 is involved in fibroblast activation and TIF, which associates with Notch1 ubiquitination and proteasome degradation.