RESUMO
Pulmonary fibrosis is a kind of fibrotic interstitial pneumonia with poor prognosis. Aging, environmental pollution, and coronavirus disease 2019 are considered as independent risk factors for pulmonary fibrogenesis. Consequently, the morbidity and mortality striking continues to rise in recent years. However, the clinical therapeutic efficacy is very limited and unsatisfactory. So it is necessary to develop a new effective therapeutic approach for pulmonary fibrosis. Human umbilical cord mesenchymal stem cells (hucMSCs) are considered as a promising treatment for various diseases because of their multiple differentiation and immunomodulatory function. The key bottleneck in the clinical application of hucMSCs therapy is the high-quality and large-scale production. This study used FloTrix miniSpin bioreactor, a three-dimensional (3D) cell culture system, for large-scale expansion of hucMSCs in vitro, and proved 3D cultured hucMSCs inhibited the differentiation of fibroblasts into myofibroblasts and myofibroblasts proliferation and migration, leading to slow down the development of pulmonary fibrosis. Further mechanistic studies clarified that hucMSCs reduced the amount of binding between circELP2 and miR-630, resulting in blocking YAP/TAZ translocation from cytoplasm to nucleus. This condition inhibited mitochondrial fusion and promoted mitochondrial fission, and ultimately improved fusion/fission balance and cellular homeostasis. To sum up, this work clarified the anti-fibrosis and mechanism of hucMSCs cultured from the 3D FloTrix miniSpin bioreactor. We hope to provide new ideas and new methods for the clinical transformation and industrialization of hucMSCs therapy.
Assuntos
Células-Tronco Mesenquimais , Dinâmica Mitocondrial , Fibrose Pulmonar , Cordão Umbilical , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Cordão Umbilical/citologia , Fibrose Pulmonar/terapia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Animais , Diferenciação Celular , Técnicas de Cultura de Células em Três Dimensões/métodos , Células Cultivadas , Proliferação de CélulasRESUMO
This study was performed to determine the effect of human umbilical cord mesenchymal stem cells (hucMSCs) treatment on pulmonary fibrosis and investigate the circFOXP1-mediated autophagic mechanism of hucMSCs treatment. Pulmonary fibrosis models were established by spraying bleomycin in mice and TGF-ß1 treatment of MRC-5 cells. Results showed that hucMSCs were retained in lung and hucMSCs treatment alleviated pulmonary fibrosis. Morphological staining indicated that hucMSCs-treated mice had thinner alveolar walls, effectively improved alveolar structure, significantly reduced alveolar inflammation, and decreased collagen deposition than control mice. Fibrotic proteins, including vimentin, α-SMA, collagens I and III, and the differentiation-related protein S100 calcium-binding protein A4 was reduced considerably in the hucMSCs-treated group. The mechanistic study revealed that the inhibition of hucMSCs treatment on pulmonary fibrogenesis depended on downregulating circFOXP1, in which hucMSCs treatment promoted circFOXP1-mediated autophagy process via blocking the nuclear human antigen R (HuR) translocation and promoting the HuR degradation, leading to a marked decrease in autophagy negative regulators EZH2, STAT1, and FOXK1. In conclusion, hucMSCs treatment significantly improved pulmonary fibrosis by downregulating the circFOXP1-HuR-EZH2/STAT1/FOXK1 autophagic axis. hucMSCs can act as an effective treatment for pulmonary fibrosis.
Assuntos
Células-Tronco Mesenquimais , Fibrose Pulmonar , Camundongos , Humanos , Animais , Fibrose Pulmonar/terapia , Fibrose , Pulmão/metabolismo , Células-Tronco Mesenquimais/metabolismo , Autofagia , Cordão Umbilical , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fator de Transcrição STAT1 , Fatores de Transcrição Forkhead/metabolismoRESUMO
Pulmonary fibrosis is a progressive disorder with poor prognosis and limited treatment options. Therefore, novel therapeutic drugs should be developed in preclinical studies. In this study, we designed and synthesized a novel compound named formononetin-7-sal ester (FS). We also investigated its anti-pulmonary fibrosis ability on transforming growth factor beta 1 (TGF-ß1)-stimulated pulmonary epithelial cells and fibroblasts in vitro and on bleomycin (BLM)-induced pulmonary fibrosis in vivo. FS strongly blocked cell proliferation and migration, which were activated by TGF-ß1, thereby reducing the expression of lung fibrosis markers, such as vimentin, alpha-smooth muscle actin (α-SMA), Snail, and collagen I and III, and increasing the expression of the epithelial cell marker E-cadherin. FS ameliorated BLM-induced pulmonary fibrosis in mice and decreased histopathologic fibrosis scores and collagen deposition. A low expression of hydroxyproline, vimentin, α-SMA, and Snail and a high expression of E-cadherin were found in FS-treated lungs compared with BLM-instilled lungs. Using the Cignal Finder 45-Pathway Reporter Array, we tested the regulation of FS in pulmonary fibrosis-associated signaling pathways and observed that FS significantly inhibited the myocyte enhancer factor-2c (MEF2c) signaling pathway. Gain- and loss-of-function studies, rescue experiments and promoter activity testing were designed to further confirm this result in vivo and in vitro. Collectively, our results demonstrated that FS prevents pulmonary fibrosis via the MEF2c signaling pathway.
Assuntos
Isoflavonas/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Antibióticos Antineoplásicos , Bleomicina , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Fibroblastos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Fatores de Transcrição MEF2/efeitos dos fármacos , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
In this pictorial review, MR imaging findings of deep infiltrating endometriosis (DIE) are illustrated together with surgical correlation. DIE can appear as irregular nodules or plaques with similar signal intensity to muscle on both T1-weighted and T2-weighted images. Hemorrhage foci and strands or stellate margins are also often noted. Restriction of diffusion can be seen on diffusion-weighted image. Fibrosis and adhesions often result in morphologic changes, such as alimentary tract tortuosity, irregular or nodular thickening of uterosacral ligaments, and partial or complete obliteration of the pouch of Douglas. After intravenous gadolinium contrast agent administration, homo- or heterogeneous mild to moderate enhancement can be observed. MR imaging can depict endometriosis lesions and extension of DIE at different anatomic locations, which is well consistent with surgical findings. Combining signal and morphological abnormalities, MR imaging can diagnose and assess the extension of DIE with high accuracy. MR imaging findings of DIE facilitate surgeons at treatment decision making and patient communication.
RESUMO
Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), play increasingly important roles in pathological processes involved in disease development. However, whether mRNAs interact with miRNAs and lncRNAs to form an interacting regulatory network in diseases remains unknown. In this study, the interaction of coexpressed mRNAs, miRNAs and lncRNAs during tumor growth factorß1activated (TGFß1) epithelialmesenchymal transition (EMT) was systematically analyzed in human alveolar epithelial cells. For EMT regulation, 24 mRNAs, 11 miRNAs and 33 lncRNAs were coexpressed, and interacted with one another. The interaction among coexpressed mRNAs, miRNAs and lncRNAs were further analyzed, and the results showed the lack of competing endogenous RNAs (ceRNAs) among them. The mutual regulation may be correlated with other modes, such as histone modification and transcription factor recruitment. However, the possibility of ceRNA existence cannot be ignored because of the generally low abundance of lncRNAs and frequent promiscuity of proteinRNA interactions. Thus, conclusions need further experimental identiï¬cation and validation. In this context, disrupting many altered disease pathways remains one of the challenges in obtaining effective pathwaybased therapy. The reason being that one specific mRNA, miRNA or lncRNA may target multiple genes that are potentially implicated in a disease. Nevertheless, the results of the present study provide basic mechanistic information, possible biomarkers and novel treatment strategies for diseases, particularly pulmonary tumor and fibrosis.
Assuntos
Células Epiteliais Alveolares/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Biologia Computacional , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Distant metastasis is the predominant pattern of gastric cancer (GC) recurrence, and is the most common cause of cancerassociated mortality. Accumulating evidence has suggested that aberrant activation of epithelialmesenchymal transition has a crucial role in the genesis, invasion and metastasis of various types of cancer, including GC. Using Cell Counting kit8 and Transwell assays, the effects of microRNA (miR)205 on the proliferation, migration and invasion of NCIH87 GC cells were determined, and the potential underlying mechanisms were explored. The results of the present study demonstrated that miR205, which has been reported to function as a tumor suppressor in various types of cancer, significantly suppressed the migration and invasion of GC cells, which may be correlated with its suppressive effects on EMT. Upon transfection with miR205, the epithelial marker CDH1 (Ecadherin) was upregulated, and the mesenchymal markers CDH2 (Ncadherin) and vimentin were suppressed. Furthermore, zincfinger Eboxbinding homeobox factor1 (ZEB1) was identified as a putative target gene of miR205 in GC, which may be associated with its suppressive effects. The results of the present study may provide novel diagnostic and therapeutic options for the treatment of human GC.
Assuntos
Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Invasividade Neoplásica/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Genes Supressores de Tumor , Humanos , Invasividade Neoplásica/patologia , Estômago/patologia , Neoplasias Gástricas/patologiaRESUMO
The aim of this study was to identify predictive factors for higher conversion ratio in opioid switching from oral oxycodone to transdermal fentanyl (TDF) in patients with cancer pain. The participants of this study were 156 hospitalized cancer patients who underwent opioid switching from oral oxycodone to TDF at the Affiliated Hospital of Binzhou Medical University between January 1st, 2010 and March 31st, 2014. Patient characteristics, modified Glasgow Prognostic Score (mGPS), daily oxycodone dose, and reasons for opioid switching were retrospectively collected. The effect of variables on the conversion ratio was analyzed by multiple regression analysis to identify the predictive factors for higher conversion ratio in opioid switching from oral oxycodone to TDF. The results showed that the mGPS (odds ratio [OR], 2.358; 95% CI 1.379-4.031; P = 0.002), the reason for opioid switching (OR, 0.497; 95% CI, 0.298-0.828; P = 0.007) and equivalent oral morphine dose (OR, 1.700; 95% CI, 1.008-2.867; P = 0.046) were found to be significant predictors requiring higher conversion ratio in opioid switching. This study indicates that higher mGPS, poor pain control before switching and higher equivalent oral morphine dose are significant predictors of a need for higher conversion ratio in opioid switching from oral oxycodone to TDF. These results could contribute to the establishment of evidence-based medicine in cancer pain relief.
RESUMO
Green tea, owing to its beneficial effect on health, is becoming more and more popular worldwide. (-)-Epigallocatechin-3-gallate (EGCG), the main ingredient of green tea polyphenols, is a known protective effect on injured neurons in neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease. Paraquat (PQ) is a widely used herbicide that possesses a similar structure to MPP(+) and is toxic to mesencephalic dopaminergic neurons. In the present study, PQ-injured PC12 cells were chosen as an in vitro cell model of Parkinson's disease and the neuroprotective effects of EGCG were investigated. The results showed that EGCG attenuated apoptosis of PC12 cells induced by PQ. The possible mechanism may be associated with maintaining mitochondrial membrane potential, inhibiting caspase-3 activity and downregulating the expression of pro-apoptotic protein Smac in cytosol. The present study supports the notion that EGCG could be used as a neuroprotective agent for treatment of neurodegenerative diseases.