Publications by authors named "Junyao Zhu"

11 Publications

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Tetrahedral framework nucleic acids promote the biological functions and related mechanism of synovium-derived mesenchymal stem cells and show improved articular cartilage regeneration activity in situ.

Bioact Mater 2022 Mar 27;9:411-427. Epub 2021 Jul 27.

Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China.

Many recent studies have shown that joint-resident mesenchymal stem cells (MSCs) play a vital role in articular cartilage (AC) in situ regeneration. Specifically, synovium-derived MSCs (SMSCs), which have strong chondrogenic differentiation potential, may be the main driver of cartilage repair. However, both the insufficient number of MSCs and the lack of an ideal regenerative microenvironment in the defect area will seriously affect the regeneration of AC. Tetrahedral framework nucleic acids (tFNAs), notable novel nanomaterials, are considered prospective biological regulators in biomedical engineering. Here, we aimed to explore whether tFNAs have positive effects on AC in situ regeneration and to investigate the related mechanism. The results of in vitro experiments showed that the proliferation and migration of SMSCs were significantly enhanced by tFNAs. In addition, tFNAs, which were added to chondrogenic induction medium, were shown to promote the chondrogenic capacity of SMSCs by increasing the phosphorylation of Smad2/3. In animal models, the injection of tFNAs improved the therapeutic outcome of cartilage defects compared with that of the control treatments without tFNAs. In conclusion, this is the first report to demonstrate that tFNAs can promote the chondrogenic differentiation of SMSCs in vitro and enhance AC regeneration in vivo, indicating that tFNAs may become a promising therapeutic for AC regeneration.
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http://dx.doi.org/10.1016/j.bioactmat.2021.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586787PMC
March 2022

Anti-inflammatory activity of curcumin-loaded tetrahedral framework nucleic acids on acute gouty arthritis.

Bioact Mater 2022 Feb 11;8:368-380. Epub 2021 Jun 11.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China.

Gouty arthritis is a very familiar inflammatory arthritis. Controlling inflammation is the key to preventing gouty arthritis. However, colchicine, the most highly represented drug used in clinical practice, has strict contraindications owing to some severe side effects. Curcumin (Cur), a natural anti-inflammatory drug, has demonstrated good safety and efficacy. However, the rapid degradation, poor aqueous solubility, and low bioavailability of Cur limit its therapeutic effect. To strengthen the effectiveness and bioavailability of Cur. Cur loaded tetrahedral framework nucleic acids (Cur-TFNAs) were synthesized to deliver Cur. Compared with free Cur, Cur-TFNAs exhibit a preferable drug stability, good biocompatibility (CCK-8 assay), ease of uptake (immunofluorescence), and higher tissue utilization (in vivo biodistribution). Most importantly, Cur-TFNAs present better anti-inflammatory effect than free Cur both in vivo and in vitro experiments through the determination of inflammation-related cytokines expression. Therefore, we believe that Cur-TFNAs have great prospects for the prevention of gout and similar inflammatory diseases.
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http://dx.doi.org/10.1016/j.bioactmat.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429917PMC
February 2022

3-Methyladenine-enhanced susceptibility to sorafenib in hepatocellular carcinoma cells by inhibiting autophagy.

Anticancer Drugs 2021 04;32(4):386-393

Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.

As an effective targeted therapy for advanced hepatocellular carcinoma (HCC), sorafenib resistance has been frequently reported in recent years, with the activation of autophagy by cancer cells under drug stress being one of the crucial reasons. Sorafenib treatment could enhance autophagy in HCC cells and autophagy is also considered as an important mechanisms of drug resistance. Therefore, the inhibition of autophagy is a potential way to improve the sensitivity and eliminate drug resistance to restore their efficacy. To determine whether autophagy is involved in sorafenib resistance and investigate its role in the regulation of HepG2 cells' (an HCC cell line) chemosensitivity to sorafenib, we simultaneously treated HepG2 with sorafenib and 3-Methyladenine (3-MA) (a common autophagy inhibitor). First, by performing cell counting kit 8 cell viability assay, Hoechst 33342 apoptosis staining, and Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis kit detection, we found that both sorafenib and 3-MA effectively inhibitted the proliferative activity of HepG2 cells and induced their apoptosis to a certain extent. This effect was significantly enhanced after these two drugs were combined, which was also confirmed by the increased expression of apoptosis-related proteins. Subsequently, by using AAV-GFP-LC3 transfection methods and transmission electron microscopy, we found that both the number and activity of autophagosomes in HepG2 cells in sorafenib and 3-MA group were significantly reduced, suggesting that autophagy activity was inhibited, and this result was consistent with the expression results of autophagy-related proteins. Therefore, we conclude that 3-MA may attenuate the acquired drug resistance of sorafenib by counteracting its induction of autophagy activity, thus enhancing its sensitivity to advanced HCC therapy.
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http://dx.doi.org/10.1097/CAD.0000000000001032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952045PMC
April 2021

Tetrahedral framework nucleic acids promote scarless healing of cutaneous wounds via the AKT-signaling pathway.

Signal Transduct Target Ther 2020 07 17;5(1):120. Epub 2020 Jul 17.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, P.R. China.

While the skin is considered the first line of defense in the human body, there are some vulnerabilities that render it susceptible to certain threats, which is an issue that is recognized by both patients and doctors. Cutaneous wound healing is a series of complex processes that involve many types of cells, such as fibroblasts and keratinocytes. This study showed that tetrahedral framework nucleic acids (tFNAs), a type of self-assembled nucleic-acid material, have the ability to promote keratinocyte(HaCaT cell line) and fibroblast(HSF cell line) proliferation and migration in vitro. In addition, tFNAs increased the secretion of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in HSF cells and reduced the production of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in HaCaT cells by activating the AKT-signaling pathway. During in vivo experiments, tFNA treatments accelerated the healing process in skin wounds and decreased the development of scars, compared with the control treatment that did not use tFNAs. This is the first study to demonstrate that nanophase materials with the biological features of nucleic acids accelerate the healing of cutaneous wounds and reduce scarring, which indicates the potential application of tFNAs in skin tissue regeneration.
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http://dx.doi.org/10.1038/s41392-020-0173-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366912PMC
July 2020

Preventive effect of tetrahedral framework nucleic acids on bisphosphonate-related osteonecrosis of the jaw.

Nanoscale 2020 Aug;12(33):17196-17202

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

Zoledronic acid (ZA) is a bisphosphonate (BP) drug that has been widely used in clinical treatments as a potent bone resorption inhibitor. In recent years, an increasing number of cases of bisphosphonate-associated osteonecrosis of the jaw (BRONJ) have been reported. This is a severe maxillofacial complication characterized clinically by bone exposure, necrosis, pain, and halitosis. Its pathogenesis is still not clear, and there is no effective clinical treatment known. Therefore, prevention of BRONJ is especially important. To provide a new research direction for the treatment of BRONJ, this study used a new tetrahedral framework nucleic acid (TFNA), which can antagonize the inhibitory effect of ZA on the differentiation and maturation of osteoclasts (OCs). In vivo and in vitro experiments showed that TFNAs at a specific concentration exhibited no cytotoxicity and could reverse the inhibition of ZA on OC differentiation and maturation, effectively inhibiting the formation of BRONJ.
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http://dx.doi.org/10.1039/d0nr03731aDOI Listing
August 2020

Sex-dependent effects of ambient PM pollution on insulin sensitivity and hepatic lipid metabolism in mice.

Part Fibre Toxicol 2020 04 22;17(1):14. Epub 2020 Apr 22.

School of Basic Medical Sciences and Public Health, Zhejiang Chinese Medical University, 548 Binwen Rd, Building 15#, Room 215, Hangzhou, 310053, China.

Background & Aims: Emerging evidence supports ambient fine particulate matter (PM) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM exposure and investigate the underlying mechanism by which PM modulates hepatic lipid metabolism.

Methods: Both male and female C57BL/6 mice were randomly assigned to ambient PM or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatography-mass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM exposure-induced metabolic disorder.

Results: Female mice were more susceptible than their male counterparts to ambient PM exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM-exposed mice as well. In addition, exposure to PM led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM-induced metabolic dysfunction.

Conclusions: Ambient PM exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.
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http://dx.doi.org/10.1186/s12989-020-00343-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178763PMC
April 2020

Tetrahedral framework nucleic acids prevent retina ischemia-reperfusion injury from oxidative stress via activating the Akt/Nrf2 pathway.

Nanoscale 2019 Nov 23;11(43):20667-20675. Epub 2019 Oct 23.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

Retinal ischemia-reperfusion (I/R) injuries are involved in the universal pathological processes of many ophthalmic diseases, including glaucoma, diabetic retinopathy, and retinal arterial occlusion. The reason is that the ischemia-reperfusion injury is accompanied by the abnormal accumulation of reactive oxygen species (ROS), which can cause damage to retinal ganglion cells (RGCs), promote their apoptosis, and finally lead to the irreversible loss of the visual field. RGCs are specialized projection neurons that are situated in the inner retinal surface of the eye, and they transmit visual images into certain areas of the brain in the form of action potentials. Therefore, any damage that affects the viability of RGCs can cause visual field defects or even irreversible vision loss. There is no effective drug treatment in clinical practice for the loss of the visual field that is caused by the oxidation and apoptosis of RGCs. Hence, finding a drug with neuroprotective and antioxidant functions is urgently needed. As a new type of nanomaterial, tetrahedral framework nucleic acids (tFNAs) exhibit outstanding biocompatibility and have been shown in our previous studies to participate in the positive regulation of cell behavior. In this experiment, we first established a cellular model of oxidative stress in RGCs with tert-butyl peroxide (TBHP). Then, we primarily explored the antioxidant and neuroprotective effects of tFNAs after TBHP-induced oxidative stress and the main mechanisms by which the tFNAs function. Our research showed that tFNAs could reduce the production of reactive oxygen species (ROS) in cells and protect the cells from oxidative stress by regulating intracellular oxidation-related enzymes. In addition, tFNAs could simultaneously improve oxidative stress-induced apoptosis significantly via affecting the expression of apoptosis-related proteins. Finally, we confirmed by western blotting that the mechanism by which tFNAs prevent damage caused by oxidative stress involves activating the Akt/Nrf2 pathway. Our findings provide new ideas for the prevention and treatment of a series of diseases that are caused by oxidative stress to RGCs.
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http://dx.doi.org/10.1039/c9nr07171gDOI Listing
November 2019

Neuroprotective and Neurotherapeutic Effects of Tetrahedral Framework Nucleic Acids on Parkinson's Disease .

ACS Appl Mater Interfaces 2019 Sep 26;11(36):32787-32797. Epub 2019 Aug 26.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , PR China.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a series of progressive motor disorders. PD is caused by dysfunction of basal ganglia, decrease of dopaminergic neurons in substantia nigra, and abnormal accumulation of Lewy bodies and Lewy neurites. Antiparkinsonian agents, which are currently used for treatment of PD, exhibit unsatisfactory effects on disease control. In recent years, tetrahedral framework nucleic acids (TFNAs) have been considered as multifunctional nanomaterials, and their scope of application has been extended to a wide range of areas. In previous studies, TFNAs were shown to exert positive effects on various cell types in processes such as cell proliferation, cell differentiation, and apoptosis. In the present study, we explored the role of TFNAs in the treatment and prevention of PD and elucidated its underlying mechanisms of action. On the basis of the experiments conducted, we demonstrated that TFNAs could inhibit and repair the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of PC12 cells through decreasing the accumulation of α-synuclein, one of the characteristic biomarkers of PD. Genes and proteins related to the AKT/PI3K signaling and mitochondrial apoptotic pathways were examined to further support this finding. Most importantly, TFNAs exhibited unexpected neuroprotective and neurorestorative effects on PC12 cells, providing a novel approach for reducing the neuropathological changes caused by PD.
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http://dx.doi.org/10.1021/acsami.9b10308DOI Listing
September 2019

Enhancement of autophagy as a strategy for development of new DNA vaccine candidates against Japanese encephalitis.

Vaccine 2019 09 6;37(37):5588-5595. Epub 2019 Aug 6.

Department of Infectious Disease, The Shengjing Hospital of China Medical University, Shenyang 110004, China. Electronic address:

For decades, an on-going concerted effort has been made to develop a universal DNA vaccine to combat the looming threat of a potential outbreak of the emerging Japanese encephalitis virus (JEV) infection. However, effective strategies are urgently required to counter poor immunogenicity and insufficient long-term protection. Recent reports have confirmed the critical role of autophagy in antigen presentation, long-term immune memory and immune responses against JEV. In this study, JEV prM and E protein with strong immunogenicity were fused with microtubule-associated protein 1 light chain 3 (LC3) encoding gene to construct an autophagy-mediated pJME-LC3 DNA vaccine. Researches indicated significant increase of autophagosomes or LC3 Ⅱ expression in pJME-LC3 transfected cells. Furthermore, prME-LC3 fused protein was observed co-localized with GFP-LC3 to autophagosomes, which means it was successfully targeted to autophagosomes. After immunizing with pJME-LC3, mice were detected highest proportion of CD3CD8 T lymphocytes, CD8 effector memory T cells (TEMs) and JEV specific cytotoxic T lymphocyte (CTL) activity to eliminate JEV. pJME-LC3 also enhanced IgG2a antibody in serum and cytokines IFN-γ, IL-12 produced by splenocytes, thus skew toward Th1 type immune response by activating the JAK2/STAT1 signaling pathway and upregulating expression of transcription factor T-bet. Notably, mice immunized with pJME-LC3 showed highest survival rate and long-lasting neutralizing antibody when challenged with virulent JEV, which were consistent with augment in percentage of CD4 central memory T cells (TCMs). In brief, our studies suggested that autophagy can be used as a optimization strategy to enhance JEV specific immune response and long-term immune memory. Our attempt will contribute towards future efforts to develop an efficacious JEV vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2019.07.093DOI Listing
September 2019

Cardioprotection of Tetrahedral DNA Nanostructures in Myocardial Ischemia-Reperfusion Injury.

ACS Appl Mater Interfaces 2019 Aug 16;11(34):30631-30639. Epub 2019 Aug 16.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China.

Acute myocardial infarction, which can be extremely difficult to treat, is the worst deadly disease around the world. Reperfusion is expedient to reverse myocardial ischemia. However, during reperfusion, reactive oxygen species (ROS) produced by myocardial ischemia-reperfusion injury (MIRI) and further cell apoptosis are the most serious challenges to cardiomyocytes. Therefore, searching for reagents that can simultaneously reduce oxidative damage and MIRI-induced apoptosis is the pivotal strategy to rescue injured cardiomyocytes. Nevertheless, current cardioprotective drugs have some shortcomings, such as cardiotoxicity, inadequate intravenous administration, or immature technology. Previous studies have shown that tetrahedral DNA nanostructures (TDNs) have biological safety with promising anti-inflammatory and antioxidative potential. However, the progress that TDNs have made in the biological behavior of cardiomyocytes has not been explored. In this experiment, a cellular model of MIRI was first established. Then, confirmed by a series of experiments, our study indicates that TDNs can significantly decrease oxidative damage and apoptosis by limiting the overexpression of ROS, along with effecting the expression of apoptosis-related proteins. In addition, Western blot analysis demonstrated that TDNs could activate the Akt/Nrf2 signaling pathway to improve the myocardial injury induced by MIRI. Above all, the antioxidant and antiapoptotic capacities of TDNs make them a potential therapeutic drug for MIRI. This study provides new ideas and directions for more homogeneous diseases induced by oxidative damage.
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http://dx.doi.org/10.1021/acsami.9b10645DOI Listing
August 2019

Application of nanodiamonds in Cu(ii)-based rhodamine B probes for NO detection and cell imaging.

J Mater Chem B 2016 May 27;4(19):3358-3364. Epub 2016 Apr 27.

Key Laboratory of Chemical Biology, Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, China.

Nitric oxide functions as an important signalling molecule in many biological systems. Nanodiamonds (NDs) have attracted enormous attention in the field of biomaterial science for biosensing applications and drug/gene delivery. In this work, one novel Cu(ii)-based rhodamine B probe for NO detection was composed which was covalently bound to the nanodiamond (ND) surface. The results showed that the covalently conjugated ND probe could detect Cu and NO sequentially with high sensitivity, high stability and good reusability compared to a free rhodamine B probe in CHCN/HEPES (pH 6.8, v/v, 1 : 1). The detection limit for NO was estimated to be 10.5 nM. In addition, the response to NO was reversible in the presence of O, which has attracted attention in the fields of biology and environmental science. Further analysis of confocal fluorescence microscopy images and the MTT assay indicated that the conjugated ND probe has favorable biocompatibility and low toxicity. This new Cu and NO selective fluorescent ND probe may have potential applications in environmental science and biology.
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http://dx.doi.org/10.1039/c6tb00524aDOI Listing
May 2016
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