RESUMO
BACKGROUND: Colorectal signet-ring cell carcinoma (SRCC) is a rare cancer with a bleak prognosis. The relationship between its clinicopathological features and survival remains incompletely elucidated. Tumor deposits (TD) have been utilized to guide the N staging in the 8th edition of American Joint Committee on Cancer (AJCC) staging manual, but their prognostic significance remains to be established in colorectal SRCC. PATIENTS AND METHODS: The subjects of this study were patients with stage III/IV colorectal SRCC who underwent surgical treatment. The research comprised two cohorts: a training cohort and a validation cohort. The training cohort consisted of 631 qualified patients from the SEER database, while the validation cohort included 135 eligible patients from four independent hospitals in China. The study assessed the impact of TD on Cancer-Specific Survival (CSS) and Overall Survival (OS) using Kaplan-Meier survival curves and Cox regression models. Additionally, a prognostic nomogram model was constructed for further evaluation. RESULTS: In both cohorts, TD-positive patients were typically in the stage IV and exhibited the presence of perineural invasion (PNI) (P < 0.05). Compared to the TD-negative group, the TD-positive group showed significantly poorer CSS (the training cohort: HR, 1.87; 95% CI, 1.52-2.31; the validation cohort: HR, 2.43; 95% CI, 1.55-3.81; all P values < 0.001). This association was significant in stage III but not in stage IV. In the multivariate model, after adjusting for covariates, TD maintained an independent prognostic value (P < 0.05). A nomogram model including TD, N stage, T stage, TNM stage, CEA, and chemotherapy was constructed. Through internal and external validation, the model demonstrated good calibration and accuracy. Further survival curve analysis based on individual scores from the model showed good discrimination. CONCLUSION: TD positivity is an independent factor of poor prognosis in colorectal SRCC patients, and it is more effective to predict the prognosis of colorectal SRCC by building a model with TD and other clinically related variables.
Assuntos
Carcinoma de Células em Anel de Sinete , Neoplasias Colorretais , Estadiamento de Neoplasias , Nomogramas , Programa de SEER , Humanos , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/cirurgia , Carcinoma de Células em Anel de Sinete/mortalidade , Feminino , Masculino , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Seguimentos , Idoso , Estudos Retrospectivos , China/epidemiologia , Invasividade Neoplásica , AdultoRESUMO
BACKGROUND: The etiology of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is not completely clear, but its pathogenesis is closely related to T helper 17 (Th17) cells. Several histone deacetylase (HDAC) inhibitors have been shown to exert potent anti-inflammatory effects and modulate Th17 cell polarization. Owing to the large variety and broad expression of HDACs, finding specific therapeutic targets for IBD is of clinical importance. METHODS: The proportions of Th17 cells and interleukin (IL)-17A produced between patients with UC and healthy volunteers were compared. The differentiation of human peripheral blood mononuclear cells (PBMCs) into Th17 cells was induced in vitro. Differentiated Th17 cells were treated with RGFP109 (RG), a selective inhibitor of HDAC1 and 3, to observe its effects on these cells. Subsequently, colitis was induced in mice and treated with RG. The proportion of Th17 cells, the severity of colitis in mice, and colon histopathology and immunohistochemistry were evaluated respectively. RESULTS: The proportion of Th17 cells and IL-17A production was significantly increased in patients with UC than in healthy individuals. RG inhibited the differentiation of human PBMCs into Th17 cells and reduced IL-17A secretion in vitro. RG-treated colitis mice had a lower Th17 ratio, mild colon inflammation, and decreased expression of HDAC1 and 3 in the colon. CONCLUSIONS: HDAC1 and 3 inhibitors can modulate the differentiation of inflammatory Th17 cells, downregulate IL-17A levels, and exert anti-inflammatory effects in experimental colitis mice, indicating that HDAC1 and 3 may be potential therapeutic targets for patients with IBD.
Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Animais , Anti-Inflamatórios/metabolismo , Diferenciação Celular , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Histona Desacetilase 1/metabolismo , Histona Desacetilase 1/farmacologia , Humanos , Inflamação/patologia , Interleucina-17 , Leucócitos Mononucleares/metabolismo , Camundongos , Células Th17/patologiaRESUMO
Mesenchymal stem cells (MSCs) are promising in idiopathic pulmonary fibrosis (IPF) therapy. However, low survival rate and ambiguous behavior of MSCs after transplantation impede their clinical translation. To this end, we have developed a new strategy to improve the survival rate and monitor the behavior of the transplanted MSCs simultaneously. In our strategy, nintedanib, a tyrosine kinase inhibitor, is employed to protect the human MSCs (hMSCs) from excessive oxidative stress responses and inflammatory environment in the damaged lung. Moreover, by labeling of the transplanted hMSCs with a computed tomography (CT) nanotracer, Au nanoparticles functionalized with polyethylenimine (PEI) and polyethylene glycol (PEG) (Au@PEI@PEG), in combination with red-emitting firefly luciferase (RfLuc), in vivo CT/bioluminescence (BL) dual-modal imaging tracking of the location, distribution, and survival of the transplanted hMSCs in presence of nintedanib were achieved, which facilitates the profound understanding of the role the stem cells play in IPF therapy.
Assuntos
Fibrose Pulmonar Idiopática , Células-Tronco Mesenquimais , Nanopartículas Metálicas , Ouro , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis , Luciferases de Vaga-Lume , Nanopartículas Metálicas/uso terapêutico , Polietilenoglicóis , Polietilenoimina , Tomografia Computadorizada por Raios XRESUMO
Gold nanoparticles (AuNPs) pose a great challenge in the development of nanotracers that can self-adaptively alter their properties in response to certain cellular environments for long-term stem cell tracking. Herein, pH-sensitive Au nanotracers (CPP-PSD@Au) are fabricated by sequential coupling of AuNPs with sulfonamide-based polymer (PSD) and cell-penetrating peptide (CPP), which can be efficiently internalized by mesenchymal stem cells (MSCs) and undergo pH-induced self-assembly in endosomes, facilitating long-term computed tomography (CT) imaging tracking MSCs in a murine model of idiopathic pulmonary fibrosis (IPF). Using the CPP-PSD@Au, the transplanted MSCs for the first time can be monitored with CT imaging for up to 35 days after transplantation into the lung of IPF mice, clearly elucidating the migration process of MSCs in vivo. Moreover, we preliminarily explored the mechanism of the CPP-PSD@Au labeled MSCs in the alleviation of IPF, including recovery of alveolar integrity, decrease of collagen deposition, as well as down-regulation of relevant cytokine level. This work facilitates our understanding of the behavior and effect of MSCs in the therapy of IPF, thereby providing an important insight into the stem cell-based treatment of lung diseases.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Nanopartículas Metálicas , Fibrose Pulmonar , Animais , Ouro , Concentração de Íons de Hidrogênio , Camundongos , Tomografia Computadorizada por Raios XRESUMO
Gold nanoparticles (AuNPs) have been widely documented as tumor radiosensitizers via enhanced energy deposition of ionizing radiation. However, the sensitization efficiency of AuNPs is still far from satisfactory owing to the irradiation on nontarget tissues and the tumor radio-resistance. To address these issues, we report herein the rational design and development of hyaluronic acid-modified Au-Ag alloy nanoparticles (Au-Ag@HA NPs) with effective tumor radiosensitization by receptor mediated tumor targeting as well as microenvironment-activated hydroxyl radicals (â¢OH) generation. In our work, Au-Ag@HA NPs were synthesized by the coreduction of HAuCl4 and AgNO3 in the presence of trisodium citrate, followed by surface modification of HA to the Au-Ag alloy NPs. HA modification affords the alloy NPs with specific targeting to 4T1 breast cancer cells overexpressing CD44 receptor, while the introduction of Ag atom imparts the alloy NPs with superior multienzyme-like activities to the monometallic AuNPs for efficient tumor catalytic therapy. More importantly, the ionizing radiation and peroxidase-like activity of Au-Ag@HA NPs boost the production of â¢OH and the release of toxic Ag+ in the tumor sites, thereby leading to effective tumor therapeutic outcome. This work provides a promising treatment paradigm for radiation/nanozyme/Ag+ combined therapy against cancer and will advance the design and development of multifunctional nanoplatforms for synergetically enhanced tumor therapy.
Assuntos
Ouro/química , Ácido Hialurônico/química , Nanopartículas Metálicas/química , Neoplasias/terapia , Prata/química , Linhagem Celular Tumoral , Quimiorradioterapia , Humanos , Estresse Oxidativo , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Microambiente TumoralRESUMO
Decreased levels of Faecalibacterium prausnitzii (F. prausnitzii), whose supernatant plays an anti-inflammatory effect, are frequently found in inflammatory bowel disease (IBD) patients. However, the anti-inflammatory products in F. prausnitzii supernatant and the mechanism have not been fully investigated. Here we found that F. prausnitzii and F. prausnitzii-derived butyrate were decreased in the intestines of IBD patients. Supplementation with F. prausnitzii supernatant and butyrate could ameliorate colitis in an animal model. Butyrate, but not other substances produced by F. prausnitzii, exerted an anti-inflammatory effect by inhibiting the differentiation of T helper 17 (Th17) cells. The mechanism underlying the anti-inflammatory effects of the butyrate produced by F. prausnitzii involved the enhancement of the acetylation-promoted degradation of c-Myc through histone deacetylase 3 (HDAC3) inhibition. In conclusion, F. prausnitzii produced butyrate to decrease Th17 differentiation and attenuate colitis through inhibiting HDAC3 and c-Myc-related metabolism in T cells. The use of F. prausnitzii may be an effective new approach to decrease the level of Th17 cells in the treatment of inflammatory diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Butiratos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Faecalibacterium prausnitzii/metabolismo , Histona Desacetilases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Células Th17/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Butiratos/química , Butiratos/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Faecalibacterium prausnitzii/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Células Th17/citologia , Células Th17/metabolismo , Ácido Trinitrobenzenossulfônico/administração & dosagemRESUMO
Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer's disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N-methyl-d-aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs. This compound is relatively selective to HDAC6 with IC50 of 0.18 µM and also maintains comparable activity on NMDAR (Ki = 0.59 µM) as memantine. Functionally, treatment with 9d increased the level of AcTubulin in MV4-11 cells and rescued PC-12 cells from H2O2-induced cytotoxicity with EC50 of 0.94 µM. Studies in mice also demonstrated that compound 9d efficiently penetrates the blood brain barrier to reach the brain tissue. Collectively, the results strongly encourage further development of 9d as a potential therapeutic agent for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
Human mesenchymal stem cells (hMSCs), due to their immune regulation and collateral secretion effects, are currently explored for potential therapy of idiopathic pulmonary fibrosis (IPF). Understanding the migration, homing, functions, and survival of transplanted hMSCs in vivo is critical to successful IPF treatment. Therefore, it is highly desired to develop noninvasive and effective imaging technologies to track the transplanted hMSCs, providing experimental basis for improving the efficacy of hMSCs in the treatment of IPF. The rational design and development of a dual-labeling strategy are reported by integrating gold nanoparticle (AuNP)-based computed tomography (CT) nanotracers and red-emitting firefly luciferase (RfLuc)-based bioluminescence (BL) tags for CT/BL multimodal imaging tracking of the transplanted hMSCs in a murine model of IPF. In this approach, the CT nanotracer is prepared by sequential coupling of AuNPs with polyethylene glycol and trans-activator of transcription (TAT) peptide (Au@TAT), and employed it to monitor the location and distribution of the transplanted hMSCs in vivo by CT imaging, while RfLuc is used to monitor hMSCs viability by BLI. This facile strategy allows for visualization of the transplanted hMSCs in vivo, thereby enabling profound understanding of the role of hMSCs in the IPF treatment, and advancing stem cell-based regenerative medicine.
Assuntos
Rastreamento de Células , Medições Luminescentes , Células-Tronco Mesenquimais/citologia , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/patologia , Tomografia Computadorizada por Raios X , Animais , Sobrevivência Celular , Ouro/química , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Camundongos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismoRESUMO
Histone deacetylases inhibitors (HDACIs) represents effective treatments for cancer. In continuing our efforts to develop novel and potent HDACIs, a series of N-hydroxycinnamamide-based HDACIs with aromatic ring and various aliphatic linker have been successfully designed and synthesized. Biological evaluations established that compounds 4h, 4i, 4j, 4l, 4r showed superior inhibition on histone deacetylase and antiproliferative activity in some solid tumor cell lines [HeLa, SK-N-BE(2), PC-3] compared to the known inhibitor SAHA. Among these analogs, 4l exhibited selectivity to HDAC1.
Assuntos
Desenho de Fármacos , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Plant-derived dietary lectins have been reported to be involved in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, diabetes, rheumatoid arthritis, and celiac disease, but little is known about the molecular mechanisms underlying lectin-induced inflammation. In this study, we showed that plant lectins can induce caspase-1 activation and IL-1ß secretion via the NLRP3 inflammasome. Lectins were internalized and subsequently escaped from the lysosome and then translocated to the endoplasmic reticulum. Endoplasmic reticulum-loaded plant lectins then triggered Ca2+ release and mitochondrial damage, and inhibition of Ca2+ release and mitochondrial reactive oxygen species by chemical inhibitors significantly suppressed NLRP3 inflammasome activation. In vivo, plant lectin-induced inflammation and tissue damage also depended on the NLRP3 inflammasome. Our findings indicate that plant lectins can act as an exogenous "danger signal" that can activate the NLRP3 inflammasome and suggest that dietary lectins might promote inflammatory diseases via the NLRP3 inflammasome.
Assuntos
Doenças Autoimunes/imunologia , Canavalia/imunologia , Inflamassomos/metabolismo , Inflamação/imunologia , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lectinas de Plantas/metabolismo , Animais , Sinalização do Cálcio , Caspase 1/metabolismo , Dieta , Retículo Endoplasmático/metabolismo , Humanos , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Lectinas de Plantas/imunologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA.
Assuntos
Antineoplásicos/síntese química , Benzamidas/química , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Benzamidas/metabolismo , Benzamidas/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Células HeLa , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-AtividadeRESUMO
Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and proliferation of gastric cancer represents the major reason for its poor prognosis. Recent evidence indicates that long non-coding RNAs play crucial roles in development and progression of gastric cancer. Long non-coding RNA differentiation antagonizing non-protein coding RNA is upregulated in hepatic cell carcinoma, but the role of lncRNA differentiation antagonizing non-protein coding RNA in gastric cancer has not been explored. In this article, we found that differentiation antagonizing non-protein coding RNA is also upregulated in gastric cancer. Experiments revealed that silencing differentiation antagonizing non-protein coding RNA significantly inhibited gastric cancer cell proliferation in vitro and in vivo. Overexpression of differentiation antagonizing non-protein coding RNA notably increases gastric cancer cell proliferation. From RNA-seq and gene ontology annotations, we found that differentiation antagonizing non-protein coding RNA influences the gene expression programs in cell metabolic and cycle process. Taken together, our findings suggest that the long non-coding RNA differentiation antagonizing non-protein coding RNA promotes the proliferation of gastric cancer and is a potential prognostic biomarker and therapeutic target in gastric cancer.
Assuntos
Biomarcadores Tumorais/biossíntese , Proliferação de Células/genética , RNA Longo não Codificante/biossíntese , Neoplasias Gástricas/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Butyrate is an energy source for colonocytes that is formed by bacterial fermentation of dietary fiber in the colon and that exerts broad anti-inflammatory activities. Although the administration of butyrate improves homeostasis in patients and ameliorates IBD (Inflammatory Bowel Disease)-related lesions and symptoms, the anti-inflammatory mechanisms of butyrate still remain unclear. To explore the impact of butyrate on Treg (Regulatory T cell)/Th17 (T helper 17 cell) differentiation and colitis in rats. METHODS: The effect of butyrate on the expression of markers related to both Tregs and Th17 cells were determined in human monocytes as well as a rat model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid. Rats were treated with butyrate in vivo, whereas the rat splenocytes and human monocytes were treated in vitro. RESULTS: We found that butyrate administration increased peripheral blood Treg cell levels as well as plasma levels of anti-Th17 cytokines (IL-10 and IL-12). Butyrate administration further suppressed IL-17 levels in both plasma and colonic mucosa, and ameliorated colonic colitis lesions in rats. This promotion of Treg activity and inhibition of IL-17 release was also observed in human venous monocytes and rat splenocytes in vitro. CONCLUSIONS: Our results suggest that butyrate plays a key role in regulating the Treg/Th17 balance and ultimately protects the colon mucosa against the development of IBD.
Assuntos
Anti-Inflamatórios/farmacologia , Butiratos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Animais , Peso Corporal , Butiratos/metabolismo , Células Cultivadas , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/patologia , Citocinas/sangue , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos Sprague-Dawley , Linfócitos T Reguladores/citologiaRESUMO
Alleviating the injury of type II alveolar epithelial cells (AEC 2s) and inhibiting the activation and differentiation of fibroblasts are significant for improving the therapeutic effect of idiopathic pulmonary fibrosis (IPF). To this aim, ionizable liposome nanoparticles (ASNPs) coloaded with antioxidant drug astaxanthin (AST) and small interfering RNA targeting transforming growth factor ß1 (siTGF-ß1) were developed for enhanced IPF therapy. ASNPs showed high loading and intracellular delivery efficiency for AST and siTGF-ß1. After the injection of ASNPs in an IPF mice model, the loaded AST largely scavenged reactive oxygen species (ROS) in the diseased lung to reduce AEC2 apoptosis, thereby ensuring the integrity of the alveolar epithelium. Meanwhile, siTGF-ß1, delivered by ASNPs, significantly silenced the expression of TGF-ß1 in fibroblasts, inhibiting the differentiation of fibroblasts into myofibroblasts as well as reducing the excessive deposition of extracellular matrix (ECM). The combined use of the two drugs exhibited an excellent synergistic antifibrotic effect and was conducive to minimizing alveolar epithelial damage. This work provides a codelivery strategy of AST and siTGF-ß1, which shows great promise for the treatment of IPF by simultaneously reducing alveolar epithelial damage and inhibiting fibroblast activation.
RESUMO
Although endoscopic necrosectomy (EN) is more frequently used to manage walled-off necrosis (WON), there is still debate over how much time should pass between the initial stent placement and the first necrosectomy. This study aims to determine the effect of performing EN within different timings after placing the initial stent on clinical outcomes for WON. A retrospective study on infected WON patients compared an early necrosectomy within one week after the initial stent placement with a necrosectomy that was postponed after a week. The primary outcomes compared the rate of clinical success and the need for additional intervention after EN to achieve WON resolution. 77 patients were divided into early and postponed necrosectomy groups. The complete resolution of WON within six months of follow-up was attained in 73.7% and 74.3% of patients in both the early and postponed groups. The early group tended to a greater need for additional intervention after EN (26.8% early necrosectomy vs. 8.3% postponed necrosectomy, P = 0.036). Our study does not demonstrate that early necrosectomy is superior to postponed necrosectomy in terms of clinical success rate, total count of necrosectomy procedures, procedure-related complications, length of hospitalization and prognosis. Conversely, patients in the postponed group received fewer additional interventions.
Assuntos
Pancreatite Necrosante Aguda , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Pancreatite Necrosante Aguda/cirurgia , Pancreatite Necrosante Aguda/patologia , Adulto , Idoso , Resultado do Tratamento , Endoscopia/métodos , Stents/efeitos adversos , Necrose , Drenagem/métodosRESUMO
Mesenchymal stem cell (MSC) therapy has been proven to be a potentially effective approach for idiopathic pulmonary fibrosis (IPF) treatment. However, this strategy is currently limited by the poor curative effect and an insufficient comprehension of the in vivo condition of the transplanted MSCs in the remedy of IPF. To address these issues, herein, a nanosystem composed of Janus Au/mesoporous silica core/shell nanoparticles (Janus NPs) is designed for effective therapeutic and real-time tracing of MSCs in MSC-based IPF therapy. The Janus NPs consist of a Au core and a pirfenidone (PFD)-loaded mesoporous silica shell asymmetrically decorated with two targeting moieties: one is reactive oxygen species (ROS)-sensitive thioketal grafted methoxy poly(ethylene glycol) (mPEG-TK), and the other is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE). The asymmetric decoration on each side of the particle allows long-term anchoring of the Janus NPs on the cell membrane to facilitate the responsive release of PFD in the ROS environment of the fibrotic lung, thereby enhancing the therapeutic efficacy of the transplanted MSCs by improving the microenvironment. Following drug release, the Janus NPs quickly enter into MSCs, achieving long-term computed tomography (CT) imaging tracing of MSCs in IPF model mice for an in-depth comprehension of the cell therapy mechanism. Overall, this work reports on Janus Au/PFD-loaded mesoporous silica core/shell NPs that combine the drug delivery and imaging tracking of MSCs, which may provide a strategy for the stem cell-based treatment of IPF.
Assuntos
Nanopartículas , Fibrose Pulmonar , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/tratamento farmacológico , Dióxido de Silício , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Honokiol (HKL), a natural extract of the bark of the magnolia tree and an activator of the mitochondrial protein sirtuin-3 (SIRT3), has been proposed to possess anti-inflammatory effects. This study investigated the inhibitory effects of HKL on T helper (Th) 17 cell differentiation in colitis. METHODS: Serum and biopsies from 20 participants with ulcerative colitis (UC) and 18 healthy volunteers were collected for the test of serum cytokines, flow cytometry analysis (FACS), and relative messenger RNA (mRNA) levels of T cell subsets, as well as the expression of SIRT3 and phosphorylated signal transducer and activator of transcription/retinoic acid-related orphan nuclear receptor γt (p-STAT3/RORγt) signal pathway in colon tissues. In vitro, naïve clusters of differentiation (CD) 4â +â T cells isolated from the mouse spleen differentiated to subsets including Th1, Th2, Th17, and regulatory T (Treg) cells. Peripheral blood monocytes (PBMCs) from healthy volunteers were induced to the polarization of Th17 cells. After HKL treatment, changes in T cell subsets, related cytokines, and transcription factors were measured. The dextran sulfate sodium (DSS)-induced colitis and interleukin (IL)-10-deficient mice were intraperitoneally injected with HKL. These experiments were conducted to study the effect of HKL on the development, cytokines, and expression of signaling pathway proteins in colitis. RESULTS: Patients with UC had higher serum IL-17 and a higher proportion of Th17 differentiation in blood compared with healthy participants; while IL-10 level and the proportion of Treg cells were lower. Higher relative mRNA levels of RORγt and a lower SIRT3 expression in colon tissues were observed. In vitro, HKL had little effect on the differentiation of naïve CD4+ T cells to Th1, Th2, or Treg cells, but it downregulated IL-17 levels and the Th17 cell ratio in CD4+ T cells from the mouse spleen and human PBMCs under Th17 polarization. Even with a STAT3 activator, HKL still significantly inhibited IL-17 levels. In DSS-induced colitis mice and IL-10 deficient mice treated with HKL, the length of the colon, weight loss, disease activity index, and histopathological scores were improved, IL-17 and IL-21 levels, and the proportion of Th17 cells were decreased. Sirtuin-3 expression was increased, whereas STAT3 phosphorylation and RORγt expression were inhibited in the colon tissue of mice after HKL treatment. CONCLUSIONS: Our study demonstrated that HKL could partially protect against colitis by regulating Th17 differentiation through activating SIRT3, leading to inhibition of the STAT3/RORγt signaling pathway. These results provide new insights into the protective effects of HKL against colitis and may facilitate the research of new drugs for inflammatory bowel disease.
Assuntos
Colite Ulcerativa , Colite , Sirtuína 3 , Humanos , Animais , Camundongos , Interleucina-17/metabolismo , Interleucina-10/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Th17 , Sirtuína 3/metabolismo , Sirtuína 3/farmacologia , Sirtuína 3/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Colite Ulcerativa/patologia , Linfócitos T Reguladores/metabolismo , Citocinas/metabolismo , Diferenciação Celular , RNA Mensageiro/metabolismo , Sulfato de Dextrana/efeitos adversosRESUMO
Mesenchymal stem cell (MSC) transplantation is emerging as a promising approach in the treatment of idiopathic pulmonary fibrosis (IPF), while it is still impeded by several challenges, including unsatisfactory treatment outcomes due to the poor survival of transplanted MSCs, and the lack of non-invasive and long-term imaging modality for tracking the behavior of MSCs. Herein, copper-based nanozyme (CuxO NPs) and gold nanoparticles (Au NPs) were encapsulated in oxidation-sensitive dextran (Oxi-Dex), a dextran derivative with reactive oxygen species (ROS)-responsiveness, forming a kind of novel nanocomposites (assigned as RSNPs) to act as ROS scavengers and computer tomography (CT) imaging tracers. After being internalized by MSCs, RSNPs enabled continuous CT imaging tracking of the transplanted MSCs for 21 days in IPF treatment, obtaining the location and distribution of the transplanted MSCs. Once MSCs were attacked by oxidative stress, the intracellular RSNPs could activate ROS clearance on demand by releasing CuxO NPs, thereby enhancing the therapeutic efficacy against IPF by improving cell survival. Taken together, a novel multifunctional RSNP was fabricated to label MSCs for CT imaging tracking and clearing superfluous ROS, presenting a promising high-efficient IPF therapy.
Assuntos
Fibrose Pulmonar Idiopática , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Nanopartículas Metálicas , Nanocompostos , Humanos , Antioxidantes , Espécies Reativas de Oxigênio , Ouro , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/terapia , Tomografia , Tomografia Computadorizada por Raios X , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
The establishment of enterprise target inventory is directly related to the forecast of drug sales volume. Accurate sales forecasting can help businesses not only set accurate target inventory but also avoid inventory backlogs and shortages. In this paper, NN technology is used to forecast sales and is optimized using the PSO algorithm, resulting in the creation of a drug sale forecast model. The model optimizes the weights and thresholds of NN using the improved PSO optimization algorithm and predicts the periodic components based on time correlation characteristics, effectively describing the trend growth and seasonal fluctuations of sales forecast data. Furthermore, the model in this paper has been creatively improved according to the needs of practical application, which has improved the shortcomings of traditional NN, such as long training time, slow convergence speed, and ease to fall into local minima, to improve performance and quality, and has received positive results in application. The experimental results show that this model has a prediction accuracy of 96.14 percent, which is 12.78 percent higher than the traditional BP model. The optimized model can be used to forecast drug sales in a practical and feasible way.
Assuntos
Algoritmos , Redes Neurais de Computação , PrevisõesRESUMO
The identification of paracrine factors secreted by transplanted mesenchymal stem cells (MSCs) during the treatment of idiopathic pulmonary fibrosis (IPF) is essential for understanding the role of MSCs in therapy. Herein, we report a facile and efficient strategy for in vivo tracking the secretion of hepatocyte growth factor (HGF) in MSCs during IPF therapy. In our strategy, a novel nanoflare tracer consisting of gold nanoparticles (AuNPs), complementary sequences and dye-labeled recognition sequences is developed. Briefly, the AuNPs are functionalized with oligonucleotide complementary sequences hybridized to the organic dye-labeled recognition sequences, where the organic fluorophores are in close proximity to the AuNPs. In the absence of targets, the dye and AuNPs are separated from each other, inducing the quenching of the fluorescence signal. However, in the presence of targets, the recognition sequences gradually fall off from the AuNPs, causing the fluorescence signal to rise. In brief, in vivo monitoring of the dynamic expression of HGF mRNA in transplanted MSCs during IPF therapy in the current work may provide new insight into the paracrine process of the transplanted MSCs, thereby advancing the MSC-based IPF therapy toward clinical applications.