Mouse bone marrow-derived Lin − -Sca-1 + endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF-or PlGF-induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivationdependent, ubiquitin-assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down-regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC-supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC.

Background: The management of various central nervous system (CNS) disorders has been challenging, due to highly compact blood-brain barrier (BBB) impedes the access of most pharmacological agents to the brain. Among multiple strategies proposed to circumvent this challenge, intranasal delivery route has sparked great interest for brain targeting in the past decades. The aim of this study was to apply scientometric method to estimate the current status and future trends of the field from a holistic perspective.Methods: All relevant publications during 1998–2020 were retrieved from the Web of Science Core Collection (SCIE, 1998-present). Two different scientometric software including VOS viewer and CiteSpace, and one online platform were used to conduct co-authorship, co-citation, and co-occurrence analysis of journals, countries, institutes, authors, references and keywords.Results: A total of 2,928 documents, including 2,456 original articles and 472 reviews, were retrieved. Our analysis revealed a significant increasing trend in the total number of scientific publications over the past 2 decades (R2 = 0.98). The United States dominated the field, reflecting in the largest amount of publications (971), the highest H-index (99), and extensive international collaboration. Jamia Hamdard contributed to most publications. Frey WH and Illum L were key researchers with the highest number of publications and citations, respectively. The International Journal of Pharmaceutics was the most influential academic journal, and Pharmacology/Pharmacy and Neurosciences/Neurology were the hottest research categories in this field. Based on keywords occurrence analysis, four main topics were identified, and the current research focus of this field has shifted from cluster 4 (pathways and mechanisms of intranasal delivery) to cluster 2 (the study of nasal drug delivery systems), especially the nanostructured and nano-sized carrier systems. Keywords burst detection revealed that the research focus on oxidative stress, drug delivery, neuroinflammation, nanostructured lipid carrier, and formulation deserves our continued attention.Conclusion: To the authors’ knowledge, this is the first scientometric analysis regarding intranasal delivery research. This study has demonstrated a comprehensive knowledge map, development landscape and future directions of intranasal delivery research, which provides a practical and valuable reference for scholars and policymakers in this field.

Background: Among the effective approaches developed for blood-brain barrier (BBB) opening, ultrasound is recognized as a non-invasive technique that can induce localized BBB opening transiently and repeatedly. This technique has aroused broad attention from researchers worldwide, and numerous articles have been published recently. However, no existing study has systematically examined this field from a scientometric perspective. The aim of this study was to summarize the knowledge structure and identify emerging trends and potential hotspots in this field.Methods: Publications related to ultrasound-induced BBB opening published from 1998 to 2020 were retrieved from Web of Science Core Collection. The search strategies were as follows: topic: (“blood brain barrier” OR “BBB”) AND topic: (ultrasound OR ultrason* OR acoustic* OR sonopora*). The document type was set to articles or reviews with language restriction to English. Three different analysis tools including one online platform, VOS viewer1.6.16, and CiteSpace V5.7.R2 software were used to conduct this scientometric study.Results: A total of 1,201 valid records were included in the final analysis. The majority of scientific publication was produced by authors from North America, Eastern Asia, and Western Europe. Ultrasound in Medicine and Biology was the most prominent journal. The USA, China, and Canada were the most productive countries. Hynynen K, and Mcdannold N were key researchers with considerable academic influence. According to analysis of keywords, four main research directions were identified: cluster 1 (microbubbles study), cluster 2 (management of intracranial tumors), cluster 3 (ultrasound parameters and mechanisms study), and cluster 4 (treatment of neurodegenerative diseases). The current research hotspot has shifted from the basic research of ultrasound and microbubbles to management of intracranial tumors and neurodegenerative diseases. Burst detection analysis showed that Parkinson's disease, doxorubicin, gold nanoparticle, glioblastoma, gene therapy, and Alzheimer's disease may continue to be the research frontiers.Conclusion: Ultrasound-induced BBB opening research is in a period of robust development. This study is a starting point, providing a comprehensive overview, development landscape, and future opportunities of this technology, which standout as a useful reference for researchers and decision makers interested in this area.

α‐ l ‐Fucosidase 1 (FUCA1), a lysosomal enzyme that catalyses the hydrolytic cleavage of the terminal fucose residue, has been reported to be involved in tumorigenesis. However, the clinical significance and biological roles of FUCA1 in glioma remain largely unknown. We analyzed FUCA1 expression according to data in Oncomine, The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases and further verified FUCA1 expression with immunohistochemistry and real‐time PCR analysis in glioma tissues. The results showed that FUCA1 overexpression was significantly associated with high‐grade glioma as well as high mortality rates in the survival analysis. Data analyzed in cBioPortal showed that alterations in FUCA1 (1.4%) were correlated with worse survival in glioblastoma multiforme patients. Functional experiments showed that downregulation of FUCA1 suppressed glioma growth in vitro and in vivo. Conversely, overexpression of FUCA1 had the opposite effects on glioma. Mechanistically, transient inhibition of FUCA1 promoted the formation of large acidic vacuoles, as revealed by staining with acridine orange, increased the ratio of LC3‐B/LC3‐A, and modified the expression of Beclin‐1 and Atg12, which are autophagic markers. Upregulation of FUCA1 attenuated starvation‐induced autophagy in glioma. In addition, lower levels of tumor‐infiltrating macrophages, including CD68 + (−30%), F4/80 + (−50%), and CD11c + macrophages (−50%), were identified in FUCA1‐downregulated glioma tissues, and CCL2/CCL5 neutralizing Abs blocked this effect. These results show that FUCA1 could serve as a potential therapeutic target for the treatment of patients with glioma by enhancing autophagy and inhibiting macrophage infiltration.

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