Exosomal miR-218 derived from mesenchymal stem cells inhibits endothelial-to-mesenchymal transition by epigenetically modulating of BMP2 in pulmonary fibrosis.

Endothelial-to-mesenchymal transition (EndMT), the process by which endothelial cells lose their characteristics and acquire mesenchymal phenotypes, participates in the pathogenic mechanism of idiopathic pulmonary fibrosis. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) has been introduced as a promising treatment in organ fibrosis. This study aimed to explore the effects as well as the molecular mechanism for hucMSC-Exo in pulmonary fibrosis. The intravenous administration of hucMSC-Exos alleviated bleomycin-induced pulmonary fibrosis in vivo. Moreover, hucMSC-Exos elevated miR-218 expression and restored endothelial properties weakened by TGF-ß in endothelial cells. Knockdown of miR-218 partially abrogated the inhibition effect of hucMSC-Exos on EndMT. Our mechanistic study further demonstrated that MeCP2 was the direct target of miR-218. Overexpressing MeCP2 aggravated EndMT and caused increased CpG islands methylation at BMP2 promoter, which lead to BMP2 post-transcriptional gene silence. Transfection of miR-218 mimic increased BMP2 expression as well, which was downregulated by overexpression of MeCP2. Taken together, these findings indicate exosomal miR-218 derived from hucMSCs may possess anti-fibrotic properties and inhibit EndMT through MeCP2/BMP2 pathway, providing a new avenue of preventive application in pulmonary fibrosis.

Model-Based Reasoning of Clinical Diagnosis in Integrative Medicine: Real-World Methodological Study of Electronic Medical Records and Natural Language Processing Methods.

BACKGROUND: Integrative medicine is a form of medicine that combines practices and treatments from alternative medicine with conventional medicine. The diagnosis in integrative medicine involves the clinical diagnosis based on modern medicine and syndrome pattern diagnosis. Electronic medical records (EMRs) are the systematized collection of patients health information stored in a digital format that can be shared across different health care settings. Although syndrome and sign information or relative information can be extracted from the EMR and content texts can be mapped to computability vectors using natural language processing techniques, application of artificial intelligence techniques to support physicians in medical practices remains a major challenge. OBJECTIVE: The purpose of this study was to investigate model-based reasoning (MBR) algorithms for the clinical diagnosis in integrative medicine based on EMRs and natural language processing. We also estimated the associations among the factors of sample size, number of syndrome pattern type, and diagnosis in modern medicine using the MBR algorithms. METHODS: A total of 14,075 medical records of clinical cases were extracted from the EMRs as the development data set, and an external test data set consisting of 1000 medical records of clinical cases was extracted from independent EMRs. MBR methods based on word embedding, machine learning, and deep learning algorithms were developed for the automatic diagnosis of syndrome pattern in integrative medicine. MBR algorithms combining rule-based reasoning (RBR) were also developed. A standard evaluation metrics consisting of accuracy, precision, recall, and F1 score was used for the performance estimation of the methods. The association analyses were conducted on the sample size, number of syndrome pattern type, and diagnosis of lung diseases with the best algorithms. RESULTS: The Word2Vec convolutional neural network (CNN) MBR algorithms showed high performance (accuracy of 0.9586 in the test data set) in the syndrome pattern diagnosis of lung diseases. The Word2Vec CNN MBR combined with RBR also showed high performance (accuracy of 0.9229 in the test data set). The diagnosis of lung diseases could enhance the performance of the Word2Vec CNN MBR algorithms. Each group sample size and syndrome pattern type affected the performance of these algorithms. CONCLUSIONS: The MBR methods based on Word2Vec and CNN showed high performance in the syndrome pattern diagnosis of lung diseases in integrative medicine. The parameters of each group's sample size, syndrome pattern type, and diagnosis of lung diseases were associated with the performance of the methods. TRIAL REGISTRATION: ClinicalTrials.gov NCT03274908; https://clinicaltrials.gov/ct2/show/NCT03274908.

Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization.

Background and aim: Modulating biological functions of endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis in ischemic vascular diseases. This study aimed to explore the role and molecular mechanisms of ß-arrestin 2 (Arrb2) in EPCs biology and angiogenic therapy. Methods: The influence of Arrb2 on postischemic neovascularization was evaluated in Arrb2-deficient mice. The proliferation, apoptosis, and various functions of EPCs were analyzed in vitro by manipulating the expression of Arrb2. Finally, the in vivo effect of Arrb2 on EPC-mediated neovascularization was investigated in a mouse model of hind-limb ischemia (HLI). Results: Arrb2-deficient mice exhibited impaired blood flow recovery based on laser Doppler measurements and reduced capillary density in the adductor muscle after unilateral HLI. Arrb2-deficient mice also showed restricted intraplug angiogenesis in subcutaneously implanted Matrigel plugs. In vitro, lentivirus-mediated Arrb2 overexpression promoted EPC proliferation, migration, adhesion, and tube formation, whereas Arrb2 knockdown had opposite effects. In addition, the overexpression of Arrb2 in EPCs protected them from hypoxia-induced apoptosis and improved intraplug angiogenesis ex vivo. Mechanistically, Arrb2 interacted with and activated extracellular signal-regulated kinase (ERK)1/2 and protein kinase B (Akt) signaling pathways. Finally, the transplantation of EPCs overexpressing Arrb2 resulted in a significantly higher blood flow restoration in ischemic hind limb and higher capillary density during histological analysis compared with control or Arrb2-knockdown EPC-treated nude mice. Conclusions: The data indicated that Arrb2 augmented EPC-mediated neovascularization through the activation of ERK and Akt signaling pathways. This novel biological function of Arrb2 might provide a potential therapeutic option to promote EPCs in the treatment of ischemic vascular diseases.

Molecular characterization of Streptococcus pneumoniae isolated from pediatric patients in Shanghai, China.

BACKGROUND: Streptococcus pneumoniae is a major cause of bacterial infection among infants and young children with high morbidity and mortality. The serotype distribution of S. pneumoniae varies with geography, time, age, and disease. AIM: We aimed to investigate the current status of molecular characteristics of S. pneumoniae strains isolated from pediatric patients in Shanghai, China. METHODS: Between 2016 and 2018, 73 clinical S. pneumoniae isolates were characterized by capsular serotype, multilocus sequence typing, antibiotic susceptibility, and resistant genes. RESULTS: The most common serotypes were 19F (39.7%), 19A (16.4%), 6A (11.0%), 14 (9.6%), and 6B (8.2%). The coverage rates of the 7-, 10- and 13-valent pneumococcal conjugate vaccines were 64.4%, 64.4%, and 91.8%, respectively. The five predominant sequence types were ST271 (37.0%), ST320 (19.2%), ST3173 (11.0%), ST876 (6.8%), and ST81 (4.1%), which were mainly associated with serotypes 19F, 19A, 6A, 14, and 23F, respectively. The rates of resistance to penicillin and ceftriaxone were 21.9% and 39.7%, respectively. All strains displayed resistance to macrolides, 54.8% of which possessed both erm(B) and mef(A/E) genes, and 41.1% carried the erm(B) gene alone. Tn2010 (41.1%) was the most common transposon. CONCLUSIONS: Clonal complex 271 (Taiwan19F-14 clone) played a dominant role in the dissemination of pneumococcal isolates. The prevalent serotypes indicated a lack of the 7-valent pneumococcal conjugate vaccine, which has not been included in national immunization programs in mainland China. The high rate of macrolide resistance made the empirical use of macrolides alone not suitable for treating pediatric pneumococcal disease.

Targeting HSP90 attenuates angiotensin II-induced adventitial remodelling via suppression of mitochondrial fission.

AIMS: Adventitial remodelling presenting with the phenotypic switch of adventitial fibroblasts (AFs) to myofibroblasts is reportedly involved in the evolution of several vascular diseases, including hypertension. In our previous study, we reported that heat shock protein 90 (HSP90) inhibition by 17-dime-thylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) markedly attenuates angiotensin II (AngII)-induced abdominal aortic aneurysm formation by simultaneously inhibiting several key signalling and transcriptional pathways in vascular smooth muscle cells; however, little is known about its role on AFs. Given that the AF phenotypic switch is likely to be associated with mitochondrial function and calcineurin (CN), a client protein of HSP90 that mediates mitochondrial fission and function, the aim of this study was to investigate whether mitochondrial fission contributes to phenotypic switch of AF, and if it does, we further aimed to determine whether HSP90 inhibition attenuates mitochondrial fission and subsequently suppresses AF transformation and adventitial remodelling in AngII-induced hypertensive mice. METHODS AND RESULTS: In primary mouse AFs, we found that CN-dependent dephosphorylation of Drp1 induced mitochondrial fission and regulated mitochondrial reactive oxygen species production, which stimulated AF proliferation, migration, and phenotypic switching in AngII-treated AFs. Moreover, AngII was found to increase the binding of HSP90 and CN in AFs, while HSP90 inhibition significantly reversed AngII-induced mitochondrial fission and AF phenotypic switching by modulating the CN-dependent dephosphorylation of Drp1. Consistent with the effects in AFs, in an animal model of AngII-induced adventitial remodelling, 17-DMAG markedly reduced mitochondrial fission, AF differentiation, vessel wall thickening, and fibrosis in the aortic adventitia, which were mediated by CN/Drp1 signalling pathways. CONCLUSIONS: Our study suggests that CN/Drp1-dependent mitochondrial fission may be essential for understanding adventitial remodelling in hypertension and that HSP90 inhibition may serve as a novel approach for the treatment of adventitial remodelling-related diseases.