RESUMO
Myocardial infarction refers to the irreversible impairment of cardiac function resulting from the permanent loss of numerous cardiomyocytes and the formation of scar tissue. This condition is caused by acute and persistent inadequate blood supply to the heart's arteries. In the treatment of myocardial infarction, Mesenchymal stem cells (MSCs) play a crucial role because of their powerful therapeutic effects. These effects primarily stem from the paracrine secretion of multiple factors by MSCs, with exosome-carried microRNAs being the most effective component in promoting cardiac function recovery after infarction. Exosome therapy has emerged as a promising cell-free treatment for myocardial infarction as a result of its relatively simple composition, low immunogenicity and controlled transplantation dose. Despite these advantages, maintaining the stability of exosomes after transplantation and enhancing their targeting effect remain significant challenges in clinical applications. In recent developments, several approaches have been designed to optimize exosome therapy. These include enhancing exosome retention, improving their ability to target specific effects, pretreating MSC-derived exosomes and employing transgenic MSC-derived exosomes. This review primarily focuses on describing the biological characteristics of exosomes, their therapeutic potential and their application in treating myocardial infarction.
Assuntos
Exossomos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , MicroRNAs , Infarto do Miocárdio , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Infarto do Miocárdio/terapia , Miócitos Cardíacos , MicroRNAs/genéticaRESUMO
BACKGROUND: Septic cardiomyopathy is a component of multiple organ dysfunction in sepsis. Mitochondrial dysfunction plays an important role in septic cardiomyopathy. Studies have shown that cyclooxygenase-2 (COX-2) had a protective effect on the heart, and prostaglandin E2 (PGE2), the downstream product of COX-2, was increasingly recognized to have a protective effect on mitochondrial function. OBJECTIVE: This study aims to demonstrate that COX-2/PGE2 can protect against septic cardiomyopathy by regulating mitochondrial function. METHODS: Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and RAW264.7 macrophages and H9C2 cells were used to simulate sepsis in vitro. The NS-398 and celecoxib were used to inhibit the activity of COX-2. ZLN005 and SR18292 were used to activate or inhibit the PGC-1α activity. The mitochondrial biogenesis was examined through the Mitotracker Red probe, mtDNA copy number, and ATP content detection. RESULTS: The experimental data suggested that COX-2 inhibition attenuated PGC-1α expression thus decreasing mitochondrial biogenesis, whereas increased PGE2 could promote mitochondrial biogenesis by activating PGC-1α. The results also showed that the effect of COX-2/PGE2 on PGC-1α was mediated by the activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Finally, the effect of COX-2/PGE2 on the heart was also verified in the septic mice. CONCLUSION: Collectively, these results suggested that COX-2/PGE2 pathway played a cardioprotective role in septic cardiomyopathy through improving mitochondrial biogenesis, which has changed the previous understanding that COX-2/PGE2 only acted as an inflammatory factor.
Assuntos
Ciclo-Oxigenase 2 , Dinoprostona , Biogênese de Organelas , Sepse , Animais , Sepse/metabolismo , Sepse/tratamento farmacológico , Camundongos , Ciclo-Oxigenase 2/metabolismo , Células RAW 264.7 , Dinoprostona/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Cardiotônicos/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Cardiomiopatias/metabolismo , Cardiomiopatias/tratamento farmacológico , Modelos Animais de Doenças , Inibidores de Ciclo-Oxigenase 2/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismoRESUMO
Reactive oxygen species (ROS) have emerged as a promising treatment option for antibacterial and biofilm eradication. However, their therapeutic efficacy is significantly hampered by the unique microenvironments of diabetic wounds. In this study, we designed and synthesized porphyrin-based Fe covalent organic frameworks (Fe-COF) through a Schiff base condensation reaction. Subsequently, Fe-COF were encapsulated with hyaluronic acid (HA) through electrostatic adsorption, resulting in a novel formulation named HA-Fe-COF for diabetic wound healing. HA-Fe-COF were engineered to respond to hyaluronidase in the infected wound, leading to the controlled release of Fe-COF. Those released Fe-COF served a dual role as photosensitizers, generating singlet oxygen and localized heating when exposed to dual light sources. Additionally, they acted as peroxidase-like nanozymes, facilitating the production of ROS through enzymatic reactions. This innovative approach enabled a synergistic therapeutic effect combining photodynamic, photothermal, and chemodynamic modalities. Furthermore, the sustained release of HA from HA-Fe-COF promoted angiogenesis, collagen deposition, and re-epithelialization during the diabetic wound healing process. This "all-in-one" strategy offers a novel approach for the development of antimicrobial and biofilm eradication strategies that minimize damage to healthy tissues in vivo.
Assuntos
Ácido Hialurônico , Estruturas Metalorgânicas , Porfirinas , Cicatrização , Cicatrização/efeitos dos fármacos , Animais , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/administração & dosagem , Pele/efeitos dos fármacos , Humanos , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Ferro/química , Fotoquimioterapia/métodos , HialuronoglucosaminidaseRESUMO
Hepatocellular carcinoma (HCC), which is a primary liver cancer subtype, has a poor prognosis due to its high degree of malignancy. The lack of early diagnosis makes systemic therapy the only hope for HCC patients with advanced disease; however, resistance to drugs is a major obstacle. In recent years, targeted molecular therapy has gained popularity as a potential treatment for HCC. An increase in reactive oxygen species (ROS), which are cancer markers and a potential target for HCC therapy, can both promote and inhibit the disease. At present, many studies have examined targeted regulation of ROS in the treatment of HCC. Here, we reviewed the latest drugs that are still in the experimental stage, including nanocarrier drugs, exosome drugs, antibody drugs, aptamer drugs and polysaccharide drugs, to provide new hope for the clinical treatment of HCC patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Espécies Reativas de OxigênioRESUMO
Calcium (Ca2+) is a second messenger in plants growth and development, as well as in stress responses. The transient elevation in cytosolic Ca2+ concentration have been reported to be involved in plants response to abiotic and biotic stresses. In plants, Ca2+-induced transcriptional changes trigger molecular mechanisms by which plants adapt and respond to environment stresses. The mechanism for transcription regulation by Ca2+ could be either rapid in which Ca2+ signals directly cause the related response through the gene transcript and protein activities, or involved amplification of Ca2+ signals by up-regulation the expression of Ca2+ responsive genes, and then increase the transmission of Ca2+ signals. Ca2+ regulates the expression of genes by directly binding to the transcription factors (TFs), or indirectly through its sensors like calmodulin, calcium-dependent protein kinases (CDPK) and calcineurin B-like protein (CBL). In recent years, significant progress has been made in understanding the role of Ca2+-mediated transcriptional regulation in different processes in plants. In this review, we have provided a comprehensive overview of Ca2+-mediated transcriptional regulation in plants in response to abiotic stresses including nutrition deficiency, temperature stresses (like heat and cold), dehydration stress, osmotic stress, hypoxic, salt stress, acid rain, and heavy metal stress.
Assuntos
Sinalização do Cálcio , Cálcio , Estresse Salino , Temperatura Baixa , Temperatura AltaRESUMO
Exosomes, small extracellular vesicles that function as a key regulator of cell-to-cell communication, are emerging as a promising candidate for bone regeneration. Here, we aimed to investigate the effect of exosomes from pre-differentiated human alveolar bone-derived bone marrow mesenchymal stromal cells (AB-BMSCs) carrying specific microRNAs on bone regeneration. Exosomes secreted from AB-BMSCs pre-differentiated for 0 and 7 days were cocultured with BMSCs in vitro to investigate their effect on the differentiation of the BMSCs. MiRNAs from AB-BMSCs at different stages of osteogenic differentiation were analyzed. BMSCs seeded on poly-L-lactic acid(PLLA) scaffolds were treated with miRNA antagonist-decorated exosomes to verify their effect on new bone regeneration. Exosomes pre-differentiated for 7 days effectively promoted the differentiation of BMSCs. Bioinformatic analysis revealed that miRNAs within the exosomes were differentially expressed, including the upregulation of osteogenic miRNAs (miR-3182, miR-1468) and downregulation of anti-osteogenic miRNAs (miR-182-5p, miR-335-3p, miR-382-5p), causing activation of the PI3K/Akt signaling pathway. The treatment of BMSC-seeded scaffolds with anti-miR-182-5p decorated exosomes demonstrated enhanced osteogenic differentiation and efficient formation of new bone. In conclusion, Osteogenic exosomes secreted from pre-differentiated AB-BMSCs were identified and the gene modification of exosomes provides great potential as a bone regeneration strategy. DATA AVAILABILITY STATEMENT: Data generated or analyzed in this paper partly are available in the GEO public data repository(http://www.ncbi.nlm.nih.gov/geo).
Assuntos
Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Humanos , Osteogênese , Exossomos/genética , Exossomos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Regeneração Óssea/genética , Células-Tronco Mesenquimais/metabolismo , Diferenciação CelularRESUMO
BACKGROUND: Recent studies have shown patient-derived tumor organoids can predict the drug response of patients with cancer. However, the prognostic value of patient-derived tumor organoid-based drug tests in predicting the progression-free survival of patients with stage IV colorectal cancer after surgery remains unknown. OBJECTIVE: This study aimed to explore the prognostic value of patient-derived tumor organoid-based drug tests in patients with stage IV colorectal cancer after surgery. DESIGN: Retrospective cohort study. SETTINGS: Surgical samples were obtained from patients with stage IV colorectal cancer at the Nanfang Hospital. PATIENTS: A total of 108 patients who underwent surgery with successful patient-derived tumor organoid culture and drug testing were recruited between June 2018 and June 2019. INTERVENTIONS: Patient-derived tumor organoid culture and chemotherapeutic drug testing. MAIN OUTCOMES MEASURES: Progression-free survival. RESULTS: According to the patient-derived tumor organoid-based drug test, 38 patients were drug sensitive and 76 patients were drug resistant. The median progression-free survival was 16.0 months in the drug-sensitive group and 9.0 months in the drug resistant group ( p < 0.001). Multivariate analyses showed that drug resistance (HR, 3.38; 95% CI, 1.84-6.21; p < 0.001), right-sided colon (HR, 3.50; 95% CI, 1.71-7.15; p < 0.001), mucinous adenocarcinoma (HR, 2.47; 95% CI, 1.34-4.55; p = 0.004), and non-R0 resection (HR, 2.70; 95% CI, 1.61-4.54; p < 0.001) were independent predictors of progression-free survival. The new patient-derived tumor organoid-based drug test model, which includes the patient-derived tumor organoid-based drug test, primary tumor location, histological type, and R0 resection, was more accurate than the traditional clinicopathological model in predicting progression-free survival ( p = 0.001). LIMITATIONS: A single-center cohort study. CONCLUSIONS: Patient-derived tumor organoids can predict progression-free survival in patients with stage IV colorectal cancer after surgery. Patient-derived tumor organoid drug resistance is associated with shorter progression-free survival, and the addition of patient-derived tumor organoid drug tests to existing clinicopathological models improves the ability to predict progression-free survival.
Assuntos
Neoplasias Colorretais , Humanos , Estudos de Coortes , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Colorretais/cirurgia , PrognósticoRESUMO
BACKGROUND: The glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with the risk of sporadic Parkinson's disease (PD). As an environmental factor, hypoxic insults may impair dopamine neurons in the substantia nigra and exacerbate PD symptoms. However, covariants of GBA and LRRK2 combined with hypoxic insults in clinical cases of Parkinsonism have not yet been reported. CASE PRESENTATION: A 69-year-old male patient with PD and his relatives were clinically characterized and sequenced using the whole-exome technique. A novel covariant, c.1448 T > C (p. L483P, rs421016) on GBA and c.691 T > C (p. S231P, rs201332859) on LRRK2 were identified in this patient who first developed bradykinesia and rigidity in the neck at one month after an acute hypoxic insult during mountaineering. The patient presented with a mask-like face, festinating gait, asymmetric bradykinesia, and moderate rigidity. These symptoms were treated with levodopa and pramipexole, resulting in a 65% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. These parkinsonian symptoms persisted and developed with hallucinations, constipation, and rapid eye movement sleep behavior disorder. After 4 years, the patient exhibited a wearing-off phenomenon and died from pulmonary infection 8 years after disease onset. His parents, wife, and siblings were not diagnosed with PD, and his son carried p. L483P without Parkinsonism-like symptoms. CONCLUSIONS: This is a case report of PD after hypoxic insult in a patient carrying a covariant of GBA and LRRK2. This study may help us understand the interaction between genetic and environmental factors in clinical PD.
Assuntos
Doença de Parkinson , Masculino , Humanos , Idoso , Doença de Parkinson/complicações , Doença de Parkinson/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Glucosilceramidase/genética , Hipocinesia , MutaçãoRESUMO
BACKGROUND: Hyperinflammation is a life-threatening condition associated with various clinical disorders characterized by excessive immune activation and tissue damage. Multiple cytokines promote the development of hyperinflammation; however, the contribution of IL-10 remains unclear despite emerging speculations for a pathological role. Clinical observations from hemophagocytic lymphohistiocytosis (HLH), a prototypical hyperinflammatory disease, suggest that IL-18 and IL-10 may collectively promote the onset of a hyperinflammatory state. OBJECTIVE: We aimed to investigate the collaborative roles of IL-10 and IL-18 in hyperinflammation. METHODS: A comprehensive plasma cytokine profile for 87 secondary HLH patients was first depicted and analyzed. We then investigated the systemic and cellular effects of coelevated IL-10 and IL-18 in a transgenic mouse model and cultured macrophages. Single-cell RNA sequencing was performed on the monocytes/macrophages isolated from secondary HLH patients to explore the clinical relevance of IL-10/IL-18-mediated cellular signatures. The therapeutic efficacy of IL-10 blockade was tested in HLH mouse models. RESULTS: Excessive circulating IL-10 and IL-18 triggered a lethal hyperinflammatory disease recapitulating HLH-like phenotypes in mice, driving peripheral lymphopenia and a striking shift toward enhanced myelopoiesis in the bone marrow. IL-10 and IL-18 polarized cultured macrophages to a distinct proinflammatory state with pronounced expression of myeloid cell-recruiting chemokines. Transcriptional characterization suggested the IL-10/IL-18-mediated cellular features were clinically relevant with HLH, showing enhanced granzyme expression and proteasome activation in macrophages. IL-10 blockade protected against the lethal disease in HLH mouse models. CONCLUSION: Coelevated IL-10 and IL-18 are sufficient to drive HLH-like hyperinflammatory syndrome, and blocking IL-10 is protective in HLH models.
Assuntos
Interleucina-10 , Interleucina-18 , Linfo-Histiocitose Hemofagocítica , Mielopoese , Animais , Camundongos , Modelos Animais de Doenças , Linfo-Histiocitose Hemofagocítica/patologiaRESUMO
MicroRNA (miR)-23b-3p is known to target various genes that are involved in cancer-related pathways. Exosomes are emerging intercellular communication agents. Exosomes secreted by cancer cells can deliver active molecules to the surrounding stromal cells, thereby influencing the recipient cells and promoting the development of cancers. However, the role of exosomal miR-23b-3p in salivary adenoid cystic carcinoma (SACC) is not yet clear. In this study, we set out to investigate the potential role of cancer-derived exosomal miR-23b-3p-related phosphatase and tensin homolog deleted on chromosome 10 in the alteration of angiogenesis and vascular permeability in SACC. We investigated the effect of exosomal miR-23b-3p on the progression of SACC. In vitro experiments indicated that exosomal miR-23b-3p led to an upregulation of vascular permeability, and reduced expression of tight junction proteins. In addition, exosomal miR-23b-3p also enhanced angiogenesis and migration. Next, the angiogenic effect of exosomal miR-23b-3p was validated in vivo, as it led to an increase in the tumor microvasculature. Furthermore, the growth rate of SACC was faster after injection of exosomes loaded with cholesterol-modified miR-23b-3p in mice. In conclusion, these results revealed that SACC cell-derived exosomes play an important role in promoting angiogenesis and local vascular microleakage of SACC by transporting miR-23b-3p, which suggests that miR-23b-3p in the exosomes may be a potential biomarker for distant metastasis of SACC. This suggests the potential of a novel therapeutic target by delivering anti-miR-23b-3p that focuses on exosomes.
Assuntos
Carcinoma Adenoide Cístico , Exossomos , MicroRNAs , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias das Glândulas Salivares , Animais , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neoplasias das Glândulas Salivares/metabolismoRESUMO
BACKGROUND: LncRNA FGF14-AS2 is a critical suppressor in breast cancer (BCa) metastasis. However, whether FGF14-AS2 plays a role in the bone metastasis of BCa remains unknown. METHODS: TRAP assay and intratibial injection were carried out to evaluate the role of FGF14-AS2 in BCa bone metastasis in vitro and in vivo. Polyribosome profiling was done to examine the translation level. RNA pulldown combined with LC/MS was performed to identify the lncRNA-binding partner, RIP, dual-luciferase assay, and Co-IP assays as well to testify these physical interactions. The prognostic value of FGF14-AS2 expression level in BCa patients was analysed using Kaplan-Meier Plotter. RESULTS: We found that FGF14-AS2 suppresses osteoclast differentiation and osteolytic metastasis of BCa. Mechanistically, FGF14-AS2 suppresses the translation of RUNX2 by inhibiting the assembly of eIF4E/eIF4G complex and the phosphorylation of eIF4E, thereby reducing the transcription of RANKL, an essential regulator of osteoclast differentiation. Moreover, FGF14-AS2 is downregulated by YTHDF2-mediated RNA degradation in an m6A-dependent manner. Clinically, patients with high YTHDF2 and low FGF14-AS2 expression levels showed worse distant metastasis-free survival (DMFS). CONCLUSIONS: FGF14-AS2 plays a crucial role in osteolytic metastasis, and may serve as a promising prognostic biomarker and therapeutic target for BCa bone metastasis.
Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Humanos , Feminino , Neoplasias da Mama/genética , RNA Longo não Codificante/genética , Biossíntese de Proteínas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Proteínas de Ligação a RNA/genéticaRESUMO
Inorganic nanoprobes have attracted increasing attention in the biomedical field due to their versatile functionalities and excellent optical properties. However, conventional nanoprobes have a relatively low retention time in the tumor and are mostly applied in the first near-infrared window (NIR-I, 650-950 nm), limiting their applications in accurate and deep tissue imaging. Herein, we develop a Janus nanoprobe, which can undergo tumor microenvironment (TME)-induced aggregation, hence, promoting tumor retention time and providing photoacoustic (PA) imaging in the second NIR (NIR-II, 950-1700 nm) window, and enhancing photodynamic therapy (PDT) effect. Ternary Janus nanoprobe is composed of gold nanorod (AuNR) coated with manganese dioxide (MnO2) and photosensitizer pyropheophorbide-a (Ppa) on two ends of AuNR, respectively, named as MnO2-AuNR-Ppa. In the tumor, MnO2 could be etched by glutathione (GSH) to release Mn2+, which is coordinated with multiple Ppa molecules to induce in situ aggregation of AuNRs. The aggregation of AuNR effectively improves the NIR-II photoacoustic signal in vivo. Moreover, the increased retention time of nanoprobes and GSH reduction in the tumor greatly improve the PDT effect. We believe that this work will inspire further research on specific in situ aggregation of inorganic nanoparticles.
Assuntos
Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Fotoquimioterapia , Glutationa , Humanos , Compostos de Manganês , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Óxidos , Técnicas Fotoacústicas/métodos , Microambiente TumoralRESUMO
BACKGROUND: Metabolic disorders are significant in the occurrence and development of malignant tumors. Changes of specific metabolites and metabolic pathways are molecular therapeutic targets. This study aims to determine the metabolic differences between oral squamous cell carcinoma (OSCC) tissues and paired adjacent noncancerous tissues (ANT) through liquid chromatography-mass spectrometry (LC-MS). SPHK1 is a key enzyme in sphingolipid metabolism. This study also investigates the potential role of SPHK1 in OSCC. MATERIALS AND METHODS: This study used LC-MS to analyze metabolic differences between OSCC tissues and paired ANT. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were applied to explain the significance of phospholipid metabolism pathways in the occurrence and development of OSCC. Through further experiments, we confirmed the oncogenic phenotypes of SPHK1 in vitro and in vivo, including proliferation, migration, and invasion. RESULTS: The sphingolipid metabolic pathway was significantly activated in OSCC, and the key enzyme SPHK1 was significantly upregulated in oral cancer tissues, predicting poor OSCC prognosis. In this study, SPHK1 overexpression was associated with high-grade malignancy and poor OSCC prognosis. SPHK1 targeted NF-κB by facilitating p65 expression to regulate OSCC tumor progression and promote metastasis. CONCLUSIONS: This study identified metabolic differences between OSCC and paired ANT, explored the carcinogenic role of overexpressed SPHK1, and revealed the association of SPHK1 with poor OSCC prognosis. SPHK1 targets NF-κB signaling by facilitating p65 expression to regulate tumor progression and promote tumor metastasis, providing potential therapeutic targets for diagnosing and treating oral tumors.
Assuntos
Neoplasias Bucais , Fosfotransferases (Aceptor do Grupo Álcool) , Carcinoma de Células Escamosas de Cabeça e Pescoço , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Fosfolipídeos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Esfingolipídeos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
Nucleophosmin (NPM1) mutations are the most frequent genetic alteration in acute myeloid leukemia (AML) and aberrant cytoplasm-dislocated NPM1 mutant is a distinct biological characterization of this disease. Our group previously reported that NPM1 mutant elevated autophagy activity and autophagy activation contributed to leukemic cell survival. However, the molecular mechanisms by which cytoplasmic NPM1 mutant involving in the autophagy pathway has not been fully elucidated. Here, we showed that Unc-51-like kinase 1 (ULK1) as a core autophagy protein was highly expressed in NPM1-mA positive OCI-AML3 cells and primary NPM1-mutated AML blasts. Meanwhile, we found that NPM1-mA could interact with ULK1 protein and positively regulated ULK1 protein levels. Mechanically, NPM1-mA promoted TRAF6-dependent K63 ubiquitination and further maintained ULK1 stability and kinase activity via miR-146a. In addition, ULK1 high expression-mediated autophagy activation and facilitated to leukemic cell proliferation. Finally, we demonstrated that restoring ULK1 expression, ULK1 inhibitor SBI-0206965 treatment and using shULK1 partially rescued the effect of NPM1-mA on autophagy and cell survival. In conclusion, our findings suggest that NPM1 mutant interacts with ULK1, and thus, maintains its protein stability, which is required for NPM1 mutant-mediated autophagic cell survival. These data extend our understanding of the functions of NPM1 mutant in the regulation of autophagy activation in NPM1-mutated AML.
Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas Nucleares/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Benzamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Estabilidade Enzimática , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , UbiquitinaçãoRESUMO
BACKGROUND: miRNAs and mRNAs have been significantly implicated in tumorigenesis and served as promising prognostic biomarkers for human cancer. Hence, this study was aimed to develop the pivotal miRNA biomarkers-based prognostic signature for salivary adenoid cystic carcinoma. METHODS: The miRNA and mRNA expression data were integrated from the gene expression omnibus database to study their involvement in salivary adenoid cystic carcinoma development and progression. Gene ontology and kyoto encyclopedia of genes and genomes were conducted to analyze the biological pathways. Reverse transcription-quantitative PCR was used to verify the expression of selected miRNAs in salivary adenoid cystic carcinoma and corresponding normal tissues. RESULTS: There were 386 differentially expressed genes: 158 upregulated and 228 downregulated genes and 102 differentially expressed miRNAs: 78 upregulated and 24 downregulated miRNAs in the salivary adenoid cystic carcinoma samples. A miRNA-mRNA network containing 11 miRNAs and 199 genes was subsequently constructed. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis revealed that the genes targeted by the 11 miRNAs were mostly involved in tumor-related pathways and processes, such as miRNAs in cancer, focal adhesion, neurotrophin signaling pathway, and the PI3K-Akt signaling pathway. Among them, 4 miRNAs (miR-375, miR-494, miR-34c-5p, and miR-331-3p) were selected to verify by reverse transcription-quantitative PCR in 36 pairs of collected salivary adenoid cystic carcinoma and adjacent nontumor samples. Overall survival analysis revealed that the higher expression of miR-331-3p was significantly associated with a worst overall survival and multivariate Cox regression analysis suggested that hsa-miR-331-3p could be an independent prognostic factor for salivary adenoid cystic carcinoma. CONCLUSION: Our results revealed that 4-miRNAs signature was a powerful prognostic biomarker for salivary adenoid cystic carcinoma, which provide a basis for exploring deeper mechanisms regarding the progression of salivary adenoid cystic carcinoma, and leading to the development of potential therapeutic strategies.
Assuntos
Carcinogênese/genética , Carcinoma Adenoide Cístico , MicroRNAs , Neoplasias das Glândulas Salivares , Carcinoma Adenoide Cístico/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , MicroRNAs/genética , Fosfatidilinositol 3-Quinases , Neoplasias das Glândulas Salivares/genéticaRESUMO
BACKGROUND AND STUDY AIMS: Anastomotic ischemia can affect healing and eventually lead to anastomotic leakage, and confocal laser endomicroscopy (CLE) can offer detailed observations at the subcellular level. We aimed to evaluate the anastomotic microcirculation in different anastomotic perfusion models using CLE. METHODS: Anastomotic perfusion models were established using twelve rabbits distributed into two groups: group A (good perfusion, n = 6) and group B (poor perfusion, n = 6). Afterward, intraoperative detection of anastomotic perfusion was carried out using CLE, and quantitative analysis of blood cells was performed. Rabbits that satisfied the criteria underwent a second exploratory operation and specimens were stained by hematoxylin and eosin. RESULTS: Enhanced with fluorescein sodium, capillaries were obviously highlighted in group A, while few capillaries were viewed in group B. Delayed development of fluorescence occurred in group B. The average flow of blood cells was 37.0 ± 5.93 per minute in group A and 6.33 ± 2.16 per minute in group B (p < 0.001). In addition, during the second exploratory surgery, rabbits with inadequate anastomotic perfusion exhibited more serious intestinal adhesion and ischemia. Anastomotic leakage and abdominal infection occurred in all rabbits in group B. CONCLUSION: CLE can realize real-time imaging of the anastomotic microcirculation and is a feasible technique for performing intraoperative evaluation in different anastomotic perfusion situations. This animal experiment provides the groundwork for future in vivo research in humans.
Assuntos
Cirurgia Colorretal , Procedimentos Cirúrgicos do Sistema Digestório , Anastomose Cirúrgica , Fístula Anastomótica , Animais , Humanos , Lasers , Microscopia Confocal , CoelhosRESUMO
Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEVs) have been demonstrated as a therapeutic agent to prevent and treat cisplatin-induced acute kidney injury (AKI). However, hucMSC-sEVs still face many problems and challenges in the repair and treatment of tissue injury, including short circulation time, insufficient targeting, and low therapeutic efficacy. Therefore, we constructed engineered hybrid vesicles fused with nanovesicles derived from human neutrophil membranes and hucMSC-sEVs, named neutrophil membrane engineered hucMSC-sEVs (NEX). NEX significantly enhanced the targeting of hucMSC-sEVs to injured kidney tissues, improved the impaired renal function via reducing pro-inflammatory cytokines expression, promoted the proliferation of renal tissue cells, and inhibited renal cell apoptosis in vivo. In addition, NEX enhanced hucMSC-sEVs uptake by NRK52E cells, but inhibited its uptake by RAW264.7 cells. Moreover, administration of NEX reduced cellular oxidative stress and promoted proliferation of NRK52E cells treated with cisplatin in vitro. In summary, our findings indicate that this design of a universal approach enhances the targeting and therapeutic efficacy of hucMSC-sEVs in kidney tissue regeneration, and provides new evidence promoting its clinical application.
Assuntos
Injúria Renal Aguda , Exossomos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/terapia , Cisplatino , Exossomos/metabolismo , Humanos , Neutrófilos , Cordão Umbilical/metabolismoRESUMO
This paper analyses environmental and economic performance of thermal utilization technologies of two different refuse derived fuel (RDF) manufactured from landfilled waste or fresh municipal waste, including incineration of landfilled RDF (I-LRDF), gasification of landfilled RDF (G-LRDF), replacement of partial coal by landfilled RDF for the cement industry (C-LRDF), incineration of municipal RDF (I-MRDF), and replacement of partial coal by municipal RDF for the cement industry (C-MRDF). The preference among the RDF utilization options is identified from the standpoints of various stakeholders by integrating the life cycle assessment (LCA) and techno-economic analysis (TEA) with the analytic hierarchy process (AHP) and technique for order preference by similarity to ideal solution (TOPSIS) approaches. RDF thermal utilization technologies bring an economic profit of $17.29â¼$35.77 per ton of waste. Especially, I-LRDF has the worst effect on ecosystem quality and human health and can yield the greatest economic profit of $35.77 per ton of landfilled waste, while I-MRDF has the least impact on environment. In terms of the five RDF thermal utilization technologies, I-MRDF has the best comprehensive performance from the perspectives of different stakeholders. The improvement of the RDF thermal utilization efficiency is the most critical factor affecting the economic benefits for all cases.
Assuntos
Resíduos de Alimentos , Incineração , Ecossistema , Instalações de Eliminação de ResíduosRESUMO
The antibiotic resistance rates of Klebsiella pneumoniae have been steadily increasing in recent years. Nevertheless, the metabolic features of the drug-resistant Klebsiella pneumoniae and its associated benefits for bacterial pathogenicity are far from expounded. This study aims to unravel the unique physiological and metabolic properties specific to drug-resistant K. pneumoniae. Using scanning electron microscopy (SEM), we observed a thicker extracellular mucus layer around a drug-resistant K. pneumonia strain (Kp-R) than a drug-sensitive K. pneumonia strain (Kp-S). Kp-R also produced more capsular polysaccharide (CPS) and biofilm, and appeared to have a significant competitive advantage when co-cultured with Kp-S. Moreover, Kp-R was easier to adhere to and invade A549 epithelial cells than Kp-S but caused less cell-viability damage according to cell counting kit-8 (CCK-8) tests. Immunofluorescence revealed that both Kp-R and Kp-S infection destroyed the tight junctions and F-actin of epithelial cells, while the damage caused by Kp-S was more severe than Kp-R. We detected the extracellular metabolites secreted by the two strains with UHPLC-Q-TOF MS to explore the critical secretion products. We identified 16 predominant compounds that were differentially expressed. Among them, inosine increased the viability of epithelial cells in a dose-dependent manner, and an A2AR antagonist can abolish such enhancement. D-mannose, which was secreted less in Kp-R, inhibited the viability of A549 cells in the range of low doses. These findings provide potential targets and research strategies for preventing and treating drug-resistant K. pneumoniae infections.
Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Células Epiteliais , Humanos , Inosina , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Pulmão , Manose/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Precise orthognathic surgical splints are important in surgical-orthodontic treatment. This study aimed to propose a standardized protocol for three-dimensional (3D)-printed splints and assess the precision of splints with different occlusal coverage on the dentition (occlusal coverage depth, OCD), thus optimizing the design of 3D-printed splints to minimize the seemingly unavoidable systematic errors. METHODS: Resin models in optimal occlusion from 19 patients were selected and scanned. Intermediate splints (ISs) and final splints (FSs) with 2-mm, 3-mm, 4-mm, and 5-mm OCDs were fabricated and grouped as IS-2, IS-3, IS-4, IS-5, FS-2, FS-3, FS-4, and FS-5, respectively. The dentitions were occluded with each splint and scanned as a whole to compare with the original occlusion. Translational and rotational deviations of the lower dentition and translational deviations of the landmarks were measured. RESULTS: For vertical translation, the lower dentitions translated inferiorly to the upper dentition in most of the splints, and the translation increased as OCD got larger. Vertical translations of the dentitions in 89.47% of IS-2, 68.42% of IS-3, 42.11% of IS-4, 10.53% of IS-5, 94.74% of FS-2, 63.16% of FS-3, 26.32% of FS-4, and 21.05% of FS-5 splints were below 1 mm, respectively. For pitch rotation, the lower dentitions rotated inferiorly and posteriorly in most groups, and the rotation increased as OCD got larger. Pitch rotations of the dentitions in 100% of IS-2, 89.47% of IS-3, 57.89% of IS-4, 52.63% of IS-5, 100.00% of FS-2, 78.95% of FS-3, 52.63% of FS-4, and 47.37% of FS-5 splints were below 2°, respectively. On the other hand, the transversal and sagittal translations, roll and yaw rotations of most groups were clinically acceptable (translation < 1 mm and rotation < 2°). The deviations of ISs and FSs showed no statistical significance at all levels of coverage (P > 0.05). CONCLUSIONS: A protocol was proposed to generate 3D-printed ISs and FSs with normalized basal planes and standardized OCDs. Deviations of the ISs and FSs were more evident in the vertical dimension and pitch rotation and had a tendency to increase as the OCD got larger. ISs and FSs with both 2-mm and 3-mm OCD are recommendable regarding the precision relative to clinical acceptability. However, considering the fabrication, structural stability, and clinical application, ISs and FSs with 3-mm OCD are recommended for accurate fitting.