Publications by authors named "Yining Xu"

27 Publications

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An overview of in vitro, ex vivo and in vivo models for studying the transport of drugs across intestinal barriers.

Adv Drug Deliv Rev 2021 May 11. Epub 2021 May 11.

University of Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue Mounier 73 B1.73.12, 1200 Brussels, Belgium. Electronic address:

Oral administration is the most commonly used route for drug delivery owing to its cost-effectiveness, ease of administration, and high patient compliance. However, the absorption of orally delivered compounds is a complex process that greatly depends on the interplay between the characteristics of the drug/formulation and the gastrointestinal tract. In this contribution, we review the different preclinical models (in vitro, ex vivo and in vivo) from their development to application for studying the transport of drugs across intestinal barriers. This review also discusses the advantages and disadvantages of each model. Furthermore, the authors have reviewed the selection and validation of these models and how the limitations of the models can be addressed in future investigations. The correlation and predictability of the intestinal transport data from the preclinical models and human data are also explored. With the increasing popularity and prevalence of orally delivered drugs/formulations, the need of sophisticated preclinical models with higher predictive capacity for absorption of oral formulations used in clinical studies will be required.
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http://dx.doi.org/10.1016/j.addr.2021.05.005DOI Listing
May 2021

Circular RNA circSIPA1L1 Contributes to Osteosarcoma Progression Through the miR-411-5p/RAB9A Signaling Pathway.

Front Cell Dev Biol 2021 22;9:642605. Epub 2021 Apr 22.

School of Medicine, Shaoxing University, Shaoxing, China.

Recently, various studies have identified circular RNAs (circRNAs) to play a significant role in tumorigenesis, thereby showing potential as novel tumor biomarkers. circSIPA1L1 is a newly discoveredcircular RNA, which is formed by back-splicing of SIPA1L1 and is found increased in osteosarcoma (OS). Nevertheless, the specific functions of circSIPA1L1 in OS remain unknown. In the present study, circSIPA1L1 was obtained from a previously reported circRNA microarray in the GEO database (GSE96964). Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the mRNA level of circSIPA1L1 in OS cell lines and tissue samples. Bioinformatics analysis, luciferase reporter assays, real-time PCR, RNA pull-down assays and RNA immunoprecipitation (RIP) were employed to verify the binding of circSIPA1L1 with miR-411-5p. Xenograft tumor models were established to identify the role of circSIPA1L1 . A series of experiments, such as western blotting, colony formation, transwell assays and anoikis assay were employed to confirm the relationship across circSIPA1L1, miR-411-5p, and RAB9A. Our study confirmed circSIPA1L1 to be upregulated in both human OS samples and OS cell lines. Mechanistically, circSIPA1L1 could serve as a miR-411-5p molecular sponge to increase RAB9A expression, which was confirmed to be a tumor promoter mediating carcinogenesis. Silencing of circSIPA1L1 attenuated the vitality, invasion, migration and proliferation of OS cell lines both and . miR-411-5p inhibition or RAB9A overexpression reversed the anti-tumor effects caused by circSIPA1L1 knockdown. Briefly, circSIPA1L1 could function as a driver gene in OS and initiate OS tumorigenesis through the miR-411-5p/RAB9A signaling pathway, which might become a potential therapeutic biomarker for OS treatment.
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http://dx.doi.org/10.3389/fcell.2021.642605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100523PMC
April 2021

Adjusted Indirect and Mixed Comparisons of Conservative Treatments for Hallux Valgus: A Systematic Review and Network Meta-Analysis.

Int J Environ Res Public Health 2021 04 6;18(7). Epub 2021 Apr 6.

Faculty of Sports Science, Ningbo University, Ningbo 315211, China.

: Hallux valgus (HV) deformity is a common, potentially debilitating deformity. And evidence with high-quality for the conservative treatments of HV deformity is still required.; AIMS: To compare the effects of different conservative treatments for hallux valgus deformity by using the method of network meta-analysis.; : A systematic review and network meta-analysis of randomized controlled trials identified by searching PubMed, EMBASE, MEDLINE, OVID, and CINAHL. The included studies should have the characteristics that: (1) participants with hallux valgus deformity of any age (2) conservative treatments (3) Reported the hallux valgus (HVA), the intermetatarsal angle (IMA), the score of the Visual Analog Scale, and the score of Foot Function Index.; : 11 studies were included in this review. The agreement between reviewers reached a kappa value of 0.75. The results of the network meta-analysis showed that a combination of exercise and toe separator, night splints, and dry needling are most likely to be the best choice for reducing the hallux valgus angle (HVA) and intermetatarsal angle, and toe separators (with or without exercise), dry needling, and manipulation (with or without ice treatment) have advantages in improving the subjective feeling of patients.; : Multi-disciplinary conservative treatments have a great potential for hallux valgus deformity. More research with high-quality is needed to give a comprehensive and reasonable scheme of a holistic and long-term treatment protocol.
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http://dx.doi.org/10.3390/ijerph18073841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038851PMC
April 2021

Exploiting the single-photon detection performance of InGaAs negative-feedback avalanche diode with fast active quenching.

Opt Express 2021 Mar;29(7):10150-10161

InGaAs/InP-based negative-feedback avalanche diodes (NFADs) for 1550 nm single-photon detection with easy-to-use and low-afterpulsing features have attracted many researchers on lidar and quantum optics. Here we present a fast active-quenching circuit specifically designed to exploit the performance of a multi-mode fiber coupled NFAD for free-running operation by a further suppression on afterpulsing effects. The quenching and recovery processes of the device were characterized using electroluminescent method and a novel dual-pulse method, respectively. Results show that the proposed circuit was capable of reducing the time required for quenching and recovery process of the NFAD by approximately 20 ns, and contributed to a reduction in the number of avalanche carriers by up to 30%. As a result, the total afterpulse probability (TAP) of the NFAD with active quenching was reduced by up to 70% compared with the condition without active quenching, and by approximately 90% compared with a standard InGaAs SPAD at the photon detection efficiency (PDE) of 20%. The TAP of the proposed detector was lower than 11% when the dead time was longer than 200 ns, 600 ns, and 2 μs at the PDE of 10%, 15%, and 25%, respectively, and the usable dead time was down to 80 ns with a TAP of 20.4% at the PDE of 10%, 1550 nm, 223 K, where the DCR was as low as 918 Hz. The low-afterpulsing, low-dead-time, low-DCR features of this compact detector makes it especially suitable for use in lidar applications.
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http://dx.doi.org/10.1364/OE.420368DOI Listing
March 2021

miR-21-5p targets SKP2 to reduce osteoclastogenesis in a mouse model of osteoporosis.

J Biol Chem 2021 Mar 31:100617. Epub 2021 Mar 31.

Department of Orthopaedic Surgery, Sir Run Shaw Hospital, Zhejiang University School of Medicine; Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. Electronic address:

Osteoporosis results from an imbalance between bone formation and bone resorption. Traditional drugs for treating osteoporosis are associated with serious side effects, and thus, new treatment methods are required. This study investigated the role of differentially expressed microRNAs during osteoclast differentiation and osteoclast activity during osteoarthritis as well as the associated underlying mechanisms. We used a microarray to screen microRNAs that decreased in the process of osteoclast differentiation, and verified miR-21-5p to decrease significantly using RT-qPCR. In follow-up experiments, we found that miR-21-5p targets SKP2 to regulate osteoclast differentiation. In vivo, ovariectomised mice were used to simulate perimenopausal osteoporosis induced by oestrogen deficiency, and miR-21-5p treatment inhibited bone resorption and maintained bone cortex and trabecular structure. These results suggest that miR-21-5p is a new therapeutic target for osteoporosis.
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http://dx.doi.org/10.1016/j.jbc.2021.100617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095171PMC
March 2021

Adjusted Indirect and Mixed Comparisons of Interventions for the Patient-Reported Outcomes Measures (PROMs) of Disabled Adults: A Systematic Review and Network Meta-Analysis.

Int J Environ Res Public Health 2021 03 1;18(5). Epub 2021 Mar 1.

Faculty of Sports Science, Ningbo University, Ningbo 315211, China.

This systematic review adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) guidelines and used the method of network meta-analysis to compare the effects of different types of interventions from different perspectives which were abilities of daily life activity, psychological health, social functioning, and overall life quality. The eligibility criteria were: (1) Participants were adults above 18 years old with disabilities; (2) Interventions could be classified into active exercise, passive therapy, psychological education, psychosocial support program, multi-disciplinary program, and usual care; (3) Outcomes should be the patient-reported outcome measures (PROMs) that could be classified into abilities of daily life activity, psychological health, social functioning, and overall life quality; (4) Randomized designed and published in English. The keywords and their search field were: (1) "people with disabilities/disability", "disabled", "handicapped", or "disable people" in titles or abstracts; (2) AND "randomized" or "randomised" in titles or abstracts; (3) NOT "design", "protocol", or "review" in titles. After searching in databases of Medline (EBSCO), PubMed, CINAHL, and Ovid, 16 studies were included. As a result, active exercise and passive therapy are most likely to be the best interventions for overall life quality, psychological education and passive therapy are most likely to be the best interventions for abilities of daily life activity, and psychosocial support programs are most likely to be the best intervention for psychological health and social functioning.
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http://dx.doi.org/10.3390/ijerph18052406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967731PMC
March 2021

Inhibition of intervertebral disc disease progression via the circPKNOX1-miR-370-3p-KIAA0355 axis.

Cell Death Discov 2021 Feb 26;7(1):39. Epub 2021 Feb 26.

Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, China.

The molecular mechanism underlying the development of intervertebral disc disease (IVDD) is not completely understood. Circular RNAs (circRNAs) play a significant role in the occurrence and development of various diseases, and studies have shown that circPKNOX1 is involved in the compensatory response of extracellular matrix synthesis and secretion of the nucleus pulposus (NP) cells. However, the mechanism through which circRNAs regulate IVDD progression remains unclear; therefore, in this study, we explored the significance of circPKNOX1 in IVDD. The expression of circRNAs in NP cells of normal and degenerative patients was detected using microarray analysis, and the role of circPKNOX1 in IVDD was confirmed using RT-qPCR. The interaction networks of circRNAs, miRNAs, and miRNA target genes were detected using bioinformatics analysis, RNA fluorescence in situ hybridization, and immunofluorescence analysis. We found that the expression of circPKNOX1 decreased in IVDD cells. The expression of circPKNOX1 in NP cells, observed using RT-qPCR and western blotting, was consistent with that observed using array screening. Overexpression of circPKNOX1 increased the expression of collagen II, aggrecan, and SOX9 and decreased that of ADAMTS4, ADAMTS-5, MMP3, and MMP13. We further demonstrated that circPKNOX1 played the role of a sponge by competitively binding miR-370-3p to reverse the inhibition of KIAA0355 expression. Our findings indicated that circPKNOX1 affected the progression of IVDD by regulating the expression of KIAA0355 via miR-370-3p. Therefore, circPKNOX1-based therapy may serve as an effective IVDD treatment strategy.
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http://dx.doi.org/10.1038/s41420-021-00420-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910476PMC
February 2021

Circ0083429 Regulates Osteoarthritis Progression via the Mir-346/ Axis.

Front Cell Dev Biol 2020 15;8:579945. Epub 2021 Jan 15.

Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Osteoarthritis (OA) is a degenerative joint disease. Currently, apart from symptomatic treatment or joint replacement, no other effective treatments for OA exist. The mechanisms underlying OA remain elusive and require further research. Circular RNAs (circRNAs) are known to be involved in many diseases; however, their function in OA is not yet fully understood. Here, we identified a novel circRNA, Circ0083429. The role of Circ0083429 in OA was confirmed via western blot (WB), quantitative real-time PCR (qRT-PCR), and immunofluorescence (IF) through knockdown and overexpression experiments. The binding of Circ0083429 to downstream miR-346 and its target gene SMAD3 was predicted via bioinformatics analysis and verified using a luciferase reporter assay and RNA pulldown experiments. Finally, the function of Circ0083429 was evaluated in mouse OA models. In our study, we found that Circ0083429 regulates the homeostasis of the extracellular matrix (ECM) in human chondrocytes. Mechanistically, Circ0083429 affects OA by regulating the mRNA level of through the sponging of microRNA (miRNA)-346. Injecting adeno-associated virus Circ0083429 into the intra-junction of the mouse knee alleviated OA. In conclusion, Circ0083429 regulates the ECM via the regulation of the downstream miRNA-346/ in human chondrocytes, which provides a new therapeutic strategy for OA.
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http://dx.doi.org/10.3389/fcell.2020.579945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843588PMC
January 2021

Effect of Multi-Modal Therapies for Kinesiophobia Caused by Musculoskeletal Disorders: A Systematic Review and Meta-Analysis.

Int J Environ Res Public Health 2020 12 16;17(24). Epub 2020 Dec 16.

Faculty of Sports Science, Ningbo University, Ningbo 315211, China.

This systematic review and meta-analysis aimed to identify the effect of multi-modal therapies that combined physical and psychological therapies for kinesiophobia caused by musculoskeletal disorders compared with uni-modal therapy of only phycological therapy or psychological therapy. The search terms and their logical connector were as following: (1) "kinesiophobia" at the title or abstract; and (2) "randomized" OR "randomized" at title or abstract; not (3) "design" OR "protocol" at the title. They were typed into the databases of Medline (EBSCO), PubMed, and Ovid, following the different input rules of these databases. The eligibility criteria were: (1) Adults with musculoskeletal disorders or illness as patients; (2) Multi-modal therapies combined physical and psychological therapy as interventions; (3) Uni-modal therapy of only physical or psychological therapy as a comparison; (4) The scores of the 17-items version of the Tampa Scale of Kinesiophobia as the outcome; (5) Randomized controlled trials as study design. As a result, 12 studies were included with a statistically significant polled effect of 6.99 (95% CI 4.59 to 9.38). Despite a large heterogeneity within studies, multi-modal therapies might be more effective in reducing kinesiophobia than the unimodal of only physical or psychological therapy both in the total and subdivision analysis. The effect might decrease with age. What's more, this review's mathematical methods were feasible by taking test-retest reliability of the Tampa Scale of Kinesiophobia into consideration.
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http://dx.doi.org/10.3390/ijerph17249439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766030PMC
December 2020

CircECE1 activates energy metabolism in osteosarcoma by stabilizing c-Myc.

Mol Cancer 2020 10 26;19(1):151. Epub 2020 Oct 26.

Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.

Background: Osteosarcoma (OS) is the most common malignant bone tumor and has a poor prognosis. The potential involvement of circular RNAs (circRNAs) in OS progression remains unexplored. Here, we report that CircECE1, a circular RNA derived from human ECE1, plays a critical role in energy metabolism in OS.

Methods: The RIP chip sequence assay was performed to confirm CircECE1, through overexpression or knockdown of CircECE1 to verify its function in 143B and U2OS. RNA immunoprecipitation and immunoprecipitation were used to verify CircECE1's regulation of protein c-Myc and co- immunoprecipitation was used to verified the competitive binding relationship between CircECE1 and SPOP. The influence of CircECE1 on energy metabolism was evaluated by seahorse experiment, western blot, and immunohistochemistry.

Results: We found that CircECE1 is highly expressed in OS tissues and cells and that CircECE1 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo. Further, CircECE1 significantly promotes glucose metabolism in OS cells in vitro and in vivo. Mechanistically, CircECE1 interacts with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation. C-Myc inhibits thioredoxin binding protein (TXNIP) transcription and subsequently activates the Warburg effect.

Conclusions: CircECE1 regulates the Warburg effect through the c-Myc/TXNIP axis. CircECE1 mediated signal transduction plays a important role in OS process and energy metabolism. These findings may identify novel targets for OS molecular therapy.
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http://dx.doi.org/10.1186/s12943-020-01269-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586679PMC
October 2020

Reducing Afterpulsing in InGaAs(P) Single-Photon Detectors with Hybrid Quenching.

Sensors (Basel) 2020 Aug 6;20(16). Epub 2020 Aug 6.

Key Laboratory of Education Ministry for Laser and Infrared System Integration Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China.

High detection efficiency appears to be associated with a high afterpulse probability for InP-based single-photon avalanche diodes. In this paper, we present a new hybrid quenching technique that combines the advantages of both fast active quenching and high-frequency gated-passive quenching, with the aim of suppressing higher-order afterpulsing effects. Our results showed that the hybrid quenching method contributed to a 10% to 85% reduction of afterpulses with a gate-free detection efficiency of 4% to 10% at 1.06 μm, with 40 ns dead time, compared with the counter-based hold-off method. With the improvement of the afterpulsing performance of high-frequency gated single-photon detectors, especially at relatively high average detection efficiencies with wide gate widths, the proposed method enables their use as high-performance free-running detectors.
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http://dx.doi.org/10.3390/s20164384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472072PMC
August 2020

Targeted nanoparticles towards increased L cell stimulation as a strategy to improve oral peptide delivery in incretin-based diabetes treatment.

Biomaterials 2020 10 17;255:120209. Epub 2020 Jun 17.

Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium. Electronic address:

The delivery of therapeutic peptides via the oral route remains one of biggest challenges in the pharmaceutical industry. Recently, we have described an alternative improved drug delivery system for peptide delivery via the oral route, consisting of a lipidic nanocapsule. Despite the striking effects observed, it is still essential to develop strategies to strengthen the nanocarriers' glucagon-like peptide-1 (GLP-1) secretory effect of the nanocarrier and/or prolong its antidiabetic effect in vivo to facilitate its translation into the clinic. For this purpose, we developed and compared different fatty acid-targeted lipid and polymeric nanoparticles and evaluated the L cell stimulation induced by the nanocarriers in murine L cells in vitro and in normal healthy mice in vivo. We further examined the antidiabetic effect in vivo in an obese/diabetic mouse model induced by high-fat diet feeding and examined the effect of the oral administration frequency. Among the tested nanocarriers, only lipid-based nanocarriers that were surface-modified with DSPE-PEG on the surface were able to significantly strengthen the biological effect of the nanocarriers. They increased endogenous GLP-1 levels up to 8-fold in vivo in normoglycemic mice. Moreover, they effectively prolonged the in vivo antidiabetic effect by normalizing the plasma glucose levels in obese/diabetic mice following long-term treatment (one month). Ultimately, the targeted nanocarriers were as effective when the administration frequency was reduced from once daily to once every other day.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116363PMC
October 2020

Oral delivery of oleuropein-loaded lipid nanocarriers alleviates inflammation and oxidative stress in acute colitis.

Int J Pharm 2020 Aug 13;586:119515. Epub 2020 Jun 13.

UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium. Electronic address:

Inflammation and oxidative stress pathways have emerged as novel targets in the management of inflammatory bowel diseases (IBD). Targeting the drug to the inflamed colon remains a challenge. Nanostructured lipid carriers (NLCs) have been reported to accumulate in inflamed colonic mucosa. The antioxidant/antiinflamatory polyphenol oleuropein (OLE) was loaded in NLCs (NLC-OLE). NLC-OLE showed to be more effective in decreasing the TNF-α secretion and intracellular reactive oxygen species (ROS) by activated macrophages (J774) compared to the conventional form of OLE. OLE efficacy was preserved within NLC-OLE ameliorating inflammation in a murine model of acute colitis: reduced levels of TNF-α and IL-6, decreased neutrophil infiltration and improved histopathology of the colon were reported. In addition, NLC-OLE enhanced the ROS scavenging activity of OLE in the colon after oral administration. These data suggest that the proposed NLC-OLE could be a promising drug delivery system for OLE in IBD treatment.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119515DOI Listing
August 2020

Circular RNA circTUBGCP3 Is Up-Regulated and Promotes Cell Proliferation, Migration and Survivability via Sponge mir-30b in Osteosarcoma.

Onco Targets Ther 2020 4;13:3729-3737. Epub 2020 May 4.

Shaoxing University School of Medicine, Shaoxing, Zhejiang 312000, People's Republic of China.

Purpose: Prevailing evidences have demonstrated that circular RNAs (circRNAs) are closely associated with various stages of carcinogenesis. However, very few studies have delineated the specific mechanism of association between circRNAs and osteosarcoma (OS). It offers a novel insight that circRNAs can be explored as a potential therapeutic strategy for OS.

Materials And Methods: In this study, circTUBGCP3 was chosen from the existing reported circRNA microarray data obtained from OS cell lines and normal bone cells. Subsequently, qRT-PCR was performed to evaluate the expression level of circTUBGCP3 in OS samples and cell lines. Functional assays were conducted to estimate the impact of circTUBGCP3 on human OS cells proliferation, vitality, survivability, and migration. Western blot, luciferase reporter and in vivo tumorigenesis assays were performed to analyze the signaling pathways underlying the interaction of circTUBGCP3, miR-30b, and Vimentin.

Results: The data indicate that circTUBGCP3 may act as a sponge of miR-30b that further alters the expression of Vimentin, and promotes the proliferation and metastatic properties of OS cells.

Conclusion: circTUBGCP3 serves as a tumor promoter in tumorigenesis by increasing the possibilities of OS initiation and proliferation.
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http://dx.doi.org/10.2147/OTT.S245366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210039PMC
May 2020

Overcoming the intestinal barrier: A look into targeting approaches for improved oral drug delivery systems.

J Control Release 2020 06 8;322:486-508. Epub 2020 Apr 8.

Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, UCLouvain, Université catholique de Louvain, 1200 Brussels, Belgium. Electronic address:

Oral drug administration is one of the most preferred and simplest routes among both patients and formulation scientists. Nevertheless, orally delivery of some of the most widely used therapeutic agents (e.g., anticancer drugs, peptides, proteins and vaccines) is still a major challenge due to the limited oral bioavailability associated with them. The poor oral bioavailability of such drugs is attributed to one or many factors, such as poor aqueous solubility, poor permeability, and enzymatic degradation. Various technological strategies (such as permeation enhancers, prodrugs and nanocarriers) have been developed to enhance the bioavailability of these drugs after oral administration. Among the different approaches, advanced and innovative drug delivery systems, especially targeting-based strategies, have garnered tremendous attention. Furthermore, the presence of numerous types of cells and solute carrier transporters throughout the gastrointestinal tract represents numerous potential targeting sites for successful oral delivery that have not yet been exploited for their full potential. This review describes different targeting strategies towards different targeting sites in the gastrointestinal tract. Additionally, exciting improvements in oral drug delivery systems with different targeting strategies (e.g., M cells for oral vaccination and L cells for type 2 diabetes mellitus) are also discussed.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.006DOI Listing
June 2020

MicroRNA-25-3p regulates osteoclasts through nuclear factor I X.

Biochem Biophys Res Commun 2020 01 15;522(1):74-80. Epub 2019 Nov 15.

Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, China; Medical College of Zhejiang University, Hangzhou, China. Electronic address:

Osteoporosis is a bone metabolic disease, characterized by loss of bone density leading to fractures. Its incidence increases with age and affects patient quality of life. Although osteoclasts play a significant role in osteoporosis, their underlying regulatory mechanisms remain unclear. In this study, we found that microRNA (miR)-25-3p negatively regulates osteoclast function through nuclear factor I X (NFIX). Overexpression of NFIX promoted osteoclast proliferation and increased the expression of the osteoclast differentiation and activity markers tartrate-resistant acid phosphatase and cathepsin K. MiR-25-3p transfection inhibited NFIX expression, which in turn inhibited osteoclast proliferation. Collectively, our results suggest that miR-25-3p promotes osteoclast activity by regulating the expression of NFIX. Therefore, targeting miR-25-3p in osteoclasts could be a promising strategy for treating skeletal disorders involving reduced bone formation.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.043DOI Listing
January 2020

DNA damage response manages cell cycle restriction of senile multipotent mesenchymal stromal cells.

Mol Biol Rep 2020 Jan 29;47(1):809-818. Epub 2019 Oct 29.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Multipotent mesenchymal stromal cells (MMSCs) are promising to treat a variety of traumatic and degenerative diseases. However, in vitro-passage aging induces cell cycle arrest and a series of genetic and biological changes, which greatly limits ex vivo cell number expansion and further clinical application of MMSCs. In most cases, DNA damage and DNA damage response (DDR) act as the main cause and executor of cellular senescence respectively. Mechanistically, DNA damage signals induce cell cycle arrest and DNA damage repair via DDR. If the DNA damage is indelible, MMSCs would entry into a permanent cell cycle arrest. It should be noted that apart from DDR signaling, certain proliferation or metabolism pathways are also occupied in DNA damage related cell cycle arrest. New findings of these aspects will also be summarized in this study. In summary, we aim to provide a comprehensive review of DDR associated cell cycle regulation and other major molecular signaling in the senescence of MMSCs. Above knowledge could contribute to improve the limited capacity of in vitro expansion of MMSCs, and then promote their clinical applications.
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http://dx.doi.org/10.1007/s11033-019-05150-6DOI Listing
January 2020

Novel strategy for oral peptide delivery in incretin-based diabetes treatment.

Gut 2020 05 10;69(5):911-919. Epub 2019 Aug 10.

Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Bruxelles, Belgium

Objective: To fulfil an unmet therapeutic need for treating type 2 diabetes by developing an innovative oral drug delivery nanosystem increasing the production of glucagon-like peptide-1 (GLP-1) and the absorption of peptides into the circulation.

Design: We developed a nanocarrier for the oral delivery of peptides using lipid-based nanocapsules. We encapsulated the GLP-1 analogue exenatide within nanocapsules and investigated in vitro in human L-cells (NCl-H716) and murine L-cells (GLUTag cells) the ability of the nanosystem to trigger GLP-1 secretion. The therapeutic relevance of the nanosystem in vivo was tested in high-fat diet (HFD)-induced diabetic mice following acute (one administration) or chronic treatment (5 weeks) in obese and diabetic mice.

Results: We demonstrated that this innovative nanosystem triggers GLP-1 secretion in both human and murine cells as well as in vivo in mice. This strategy increases the endogenous secretion of GLP-1 and the oral bioavailability of the GLP-1 analogue exenatide (4% bioavailability with our nanosystem).The nanosystem synergizes its own biological effect with the encapsulated GLP-1 analogue leading to a marked improvement of glucose tolerance and insulin resistance (acute and chronic). The chronic treatment decreased diet-induced obesity, fat mass, hepatic steatosis, together with lower infiltration and recruitment of immune cell populations and inflammation.

Conclusion: We developed a novel nanosystem compatible with human use that synergizes its own biological effect with the effects of increasing the bioavailability of a GLP-1 analogue. The effects of the formulation were comparable to the results observed for the marketed subcutaneous formulation. This nanocarrier-based strategy represents a novel promising approach for oral peptide delivery in incretin-based diabetes treatment.
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http://dx.doi.org/10.1136/gutjnl-2019-319146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229891PMC
May 2020

Modified Implantation of Self-Adhesive Mesh in Laparoscopic Total Extraperitoneal Inguinal Hernia Repair.

J Laparoendosc Adv Surg Tech A 2019 Aug 13;29(8):1042-1045. Epub 2019 Apr 13.

2Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.

The self-adhesive mesh has become increasingly popular since its launch and has been proven to be reliable in laparoscopic hernia reparation. However, self-adhesive mesh may encounter unexpected adhesions during operation because one side of the mesh was covered with microgrips. Performing a modified technique of self-adhesive mesh implantation to avoid unexpected adhesions to the mesh itself and to the surrounding tissues in the operation space. We carried out a modified self-adhesive mesh implantation during May 2017 and March 2018. The modification was using a plastic membrane to cover the microgrips side of the mesh, and then rolling up the mesh to a cigarette shape. The mesh was inserted into the groin through a 10 mm trocar, and it was opened up with the membrane being removed meanwhile. A total of 21 cases of laparoscopic total extraperitoneal inguinal hernia repair were successfully performed. The mesh could be conveniently put on the right place with no unexpected adhesions and the operation time was greatly shortened by using this modified technique. Putting a plastic membrane on the microgrips side of the self-adhesive mesh could avoid the mesh adhering itself when rolling up and could be easy to spread up the mesh in the operative field without unexpected adhesions, which simplified the surgical process and shortened the surgical duration.
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http://dx.doi.org/10.1089/lap.2018.0783DOI Listing
August 2019

Novel Solid Lipid Nanoparticle with Endosomal Escape Function for Oral Delivery of Insulin.

ACS Appl Mater Interfaces 2018 Mar 8;10(11):9315-9324. Epub 2018 Mar 8.

Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy , Sichuan University , No. 17, Block 3, Southern Renmin Road , Chengdu 610041 Sichuan , China.

Although nanoparticles (NPs) have been demonstrated as promising tools for improving oral absorption of biotherapeutics, most of them still have very limited oral bioavailability. Lyso-endosomal degradation in epithelial cells is one of the important but often-neglected physiological barriers, limiting the transport of cargoes across the intestinal epithelium. We herein reported a solid lipid nanoparticle (SLN) platform with a unique feature of endosomal escape for oral protein drug delivery. The SLNs consisted of a solid-lipid shell, which contained an endosomal escape agent (GLFEAIEGFIENGWEGMIDGWYG, HA2), and an aqueous core that is loaded with insulin (INS HA2-O-SLNs). SLNs without and with the HA2 peptide in the aqueous core (INS SLNs and INS HA2-W-SLNs, respectively) were used as the control groups. Our study showed that INS HA2-O-SLNs effectively facilitated the escape of the loaded insulin from the acidic endosomes, which preserved the biological activity of insulin to a greater extent during the intracellular transport. The spatial location of the HA2 peptide was demonstrated to determine the endosomal escape efficiency. As demonstrated in the intracellular trafficking of SLNs, INS HA2-O-SLNs displayed much less distribution in late endosomes and lysosomes. Meanwhile, insulin in INS HA2-O-SLNs exhibited the highest transepithelial permeation efficiency, with 2.19 and 1.72 folds higher accumulated amount in the basolateral side as compared to that in INS SLNs and INS HA2-W-SLNs. In addition, insulin from INS HA2-O-SLNs exhibited the highest insulin permeation in various regions of small intestines. INS HA2-O-SLNs generated an excellent hypoglycemic response following oral administration in diabetic rats. Thus, such functional SLNs demonstrated a great potency for oral delivery of peptide/protein drugs.
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http://dx.doi.org/10.1021/acsami.8b00507DOI Listing
March 2018

Size Effect on Lipid Nanocapsule-Mediated GLP-1 Secretion from Enteroendocrine L Cells.

Mol Pharm 2018 01 15;15(1):108-115. Epub 2017 Dec 15.

Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain , 1200 Brussels, Belgium.

L cells are enteroendocrine cells located throughout the gastrointestinal tract that secrete physiologically important peptides. The most characterized peptides secreted by L cells are the peptide YY (PYY) and the glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). These peptides are released rapidly into the circulation after oral nutrient ingestion. Recently, lipid-based nanoparticles (NP) have been described as triggers for GLP-1 secretion by L cells. NP physicochemical properties play a key role in the NP-cell interaction, and drive NP cell internalization. We herein hypothesize that lipid-based NP with appropriate size would not only be able to deliver drugs into blood circulation but also act like endogenous ligands to stimulate GLP-1 secretion. We tested five different size (25, 50, 100, 150, and 200 nm) lipid nanocapsules (LNC) on murine L cells in vitro to confirm this hypothesis. Our study showed that GLP-1 secretion was induced only by the 200 nm size LNC, highlighting the importance of LNC particle size on the secretion of GLP-1 by L cells. The different formulations did not affect proglucagon mRNA expression, suggesting that there was not an increased GLP-1 synthesis. As a proof of concept, we further demonstrated in normoglycemic mice that 200 nm LNC administration increases GLP-1 levels by 4- and 3-fold compared to untreated control mice 60 and 180 min after the administration, respectively. Our study suggests that 200 nm LNC as a nanocarrier to encapsulate drug candidates and as a ligand to induce endogenous GLP-1 secretion might represent a promising strategy for type 2 diabetes mellitus treatment.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00742DOI Listing
January 2018

PICALM rs3851179 Variant Confers Susceptibility to Alzheimer's Disease in Chinese Population.

Mol Neurobiol 2017 07 5;54(5):3131-3136. Epub 2016 Apr 5.

School of Life Science and Technology, Harbin Institute of Technology, Room 415, Building 2E, Science Park, Yikuang Street, Nangang District, Harbin, 150080, China.

The association between PICALM rs3851179 variant and Alzheimer's disease (AD) has been well established by previous genome-wide association studies (GWAS) and candidate gene studies in European population. Recent studies investigated the association between PICALM rs3851179 and AD susceptibility in Chinese population. However, these studies reported consistent and inconsistent results. Here, we selected 9435 samples including 3704 AD cases and 5731 controls from previous studies and evaluated this association using a meta-analysis method for additive model. We did not observe significant genetic heterogeneity in Chinese population. Our results indicate significant association between PICALM rs3851179 and AD in Chinese population. The sensitivity analysis indicates that the association between rs3851179 and AD did not vary substantially. The regression analysis suggests no significant publication bias. In summary, this updated meta-analysis highlights the involvement of PICALM rs3851179 variant in Alzheimer's disease susceptibility in Chinese population.
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http://dx.doi.org/10.1007/s12035-016-9886-2DOI Listing
July 2017

PICALM rs3851179 Variant and Alzheimer's Disease in Asian Population.

Neuromolecular Med 2016 06 17;18(2):157. Epub 2016 Mar 17.

School of Life Science and Technology, Harbin Institute of Technology, Room 415, Building 2E, Science Park, Yikuang Street, Nangang District, Harbin, 150080, China.

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http://dx.doi.org/10.1007/s12017-016-8389-7DOI Listing
June 2016

The transport mechanism of integrin αvβ3 receptor targeting nanoparticles in Caco-2 cells.

Int J Pharm 2016 Mar 16;500(1-2):42-53. Epub 2016 Jan 16.

Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China. Electronic address:

As for the existence of epithelium barrier, accelerating the transport remains huge challenges for orally delivered protein and peptide drugs into blood circulation. Modifying nanopaticles (NPs) with targeting peptides can enhance the intestinal absorption of loaded macromolecular drugs. However, the transport process, which mainly means how the NPs pass through the apical membrane and the basolateral side and then enter into blood circulation, is needed comprehensive investigation. In this study, we systemically studied the transport mechanisms in Caco-2 cell model of trimethyl chitosan based NPs (TMC NPs) before and after modification of FQS, an integrin αvβ3 receptor targeting peptide. Our results showed FQS peptide mediated multiple endocytosis pathways and could activate integrin αvβ3 receptor by interacting with FAK and Src-family kinases to induce receptor-mediated endocytosis of the NPs. Then, both endocytosed NPs could transport from early endosome to lysososmes via late endosomes/lysosome pathway, as well as to recycling endosomes and Golgi apparatus through early endosome/recycling endosomes and Golgi apparatus/recycling endosomes/plasma membrane pathways, respectively. After FQS peptide modification, the endocytosis subpathways of NPs have been changed, and more pathways are involved in exocytosis process for FQS-modified NPs compared with non-modified NPs. Our study indicated the ligand modification could enhance the uptake and transport by altering some pathways in whole transport process of NPs.
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http://dx.doi.org/10.1016/j.ijpharm.2016.01.028DOI Listing
March 2016

Goblet cell targeting nanoparticle containing drug-loaded micelle cores for oral delivery of insulin.

Int J Pharm 2015 Dec 2;496(2):993-1005. Epub 2015 Nov 2.

Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China. Electronic address:

Oral administration of insulin remains a challenge due to its poor enzymatic stability and inefficient permeation across epithelium. We herein developed a novel self-assembled polyelectrolyte complex nanoparticles by coating insulin-loaded dodecylamine-graft-γ-polyglutamic acid micelles with trimethyl chitosan (TMC). The TMC material was also conjugated with a goblet cell-targeting peptide to enhance the affinity of nanoparticles with epithelium. The developed nanoparticle possessed significantly enhanced colloid stability, drug protection ability and ameliorated drug release profile compared with graft copolymer micelles or ionic crosslinked TMC nanoparticles. For in vitro evaluation, Caco-2/HT29-MTX-E12 cell co-cultures, which composed of not only enterocyte-like cells but also mucus-secreting cells and secreted mucus layer, were applied to mimic the epithelium. Intracellular uptake and transcellular permeation of encapsulated drug were greatly enhanced for NPs as compared with free insulin or micelles. Goblet cell-targeting modification further increased the affinity of NPs with epithelium with changed cellular internalization mechanism. The influence of mucus on the cell uptake was also investigated. Ex vivo performed with rat mucosal tissue demonstrated that the nanoparticle could facilitate the permeation of encapsulated insulin across the intestinal epithelium. In vivo study preformed on diabetic rats showed that the orally administered nanoparticles elicited a prolonged hypoglycemic response with relative bioavailability of 7.05%.
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http://dx.doi.org/10.1016/j.ijpharm.2015.10.078DOI Listing
December 2015

A novel ligand conjugated nanoparticles for oral insulin delivery.

Drug Deliv 2016 Jul 23;23(6):2015-25. Epub 2015 Jul 23.

a Key Laboratory of Drug Targeting and Drug Delivery System , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , P.R. China.

In order to enhance the interaction between nanocarrier and gastrointestinal epithelial cells, we developed nanoparticles (NPs) modified with targeting ligand FQSIYPpIK (FQS), which specifically interact with integrin αvβ3 receptor expressing on the intestinal epithelium. The targeting NPs were prepared by coating the insulin-loaded poly(lactide-co-glycolide)-monomethoxy-poly(polyethylene glycol) micelle cores with FQS modified trimethyl chitosan chloride. In in vitro study, the fabricated NPs showed ameliorated drug release profile and improved enzymatic stability compared with micelles alone. In the integrin αvβ3 receptor over-expressed Caco-2 cells model, FQS modified NPs exhibited significantly accelerated intracellular uptake due to the active ligand-receptor mediation. Meanwhile, the targeting NPs also showed enhanced transport across the Caco-2 monolayer cells via both transcellular and paracellular pathways. Besides, orally administered FQS modified NPs produced a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Both in vitro and in vivo results demonstrated the FQS peptide modified NPs as promising intestinal cell-targeting nanocarriers for efficient oral delivery of insulin.
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http://dx.doi.org/10.3109/10717544.2015.1058433DOI Listing
July 2016

Referrals for positive tuberculin tests in new health care workers and students: a retrospective cohort study.

BMC Public Health 2010 Jan 20;10:28. Epub 2010 Jan 20.

Montreal Chest Institute, 3650 St. Urbain Street, Montreal, Quebec, Canada.

Background: Documentation of test results for latent tuberculosis (TB) infection is important for health care workers and students before they begin work. A negative result provides a baseline for comparison with future tests. A positive result affords a potential opportunity for treatment of latent infection when appropriate. We sought to evaluate the yield of the referral process for positive baseline tuberculin tests, among persons beginning health care work or studies.

Methods: Retrospective cohort study. We reviewed the charts of all new health care students and workers referred to the Montreal Chest Institute in 2006 for positive baseline tuberculin skin tests (> or =10 mm). Health care workers and students evaluated for reasons other than positive baseline test results were excluded.

Results: 630 health care students and workers were evaluated. 546 (87%) were foreign-born, and 443 (70%) reported previous Bacille Calmette-Guérin (BCG) vaccination. 420 (67%) were discharged after their first evaluation without further treatment. 210 (33%) were recommended treatment for latent TB infection, of whom 165 (79%) began it; of these, 115 (70%) completed adequate treatment with isoniazid or rifampin. Treatment discontinuation or interruption occurred in a third of treated subjects, and most often reflected loss to follow-up, or abdominal discomfort. No worker or student had active TB.

Conclusions: Only a small proportion of health care workers and students with positive baseline tuberculin tests were eligible for, and completed treatment for latent TB infection. We discuss recommendations for improving the referral process, so as to better target workers and students who require specialist evaluation and treatment for latent TB infection. Treatment adherence also needs improvement.
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http://dx.doi.org/10.1186/1471-2458-10-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091546PMC
January 2010