Publications by authors named "Chenghao Gao"

10 Publications

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Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Promotes Inflammation and Accelerates Osteoarthritis by Activating β-Catenin.

Front Cell Dev Biol 2021 9;9:646386. Epub 2021 Apr 9.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Osteoarthritis (OA) is a chronic articular disease characterized by cartilage degradation, subchondral bone remodeling and osteophyte formation. Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) has not been fully investigated in the pathogenesis of OA. In this study, we found that SHP2 expression was significantly increased after interleukin-1β (IL-1β) treatment in primary mouse chondrocytes. Inhibition of SHP2 using siRNA reduced MMP3, MMP13 levels, but increased AGGRECAN, COL2A1, SOX9 expression . On the contrary, overexpression of SHP2 exerted the opposite results and promoted cartilage degradation. Mechanistically, SHP2 activated Wnt/β-catenin signaling possibly through directly binding to β-catenin. SHP2 also induced inflammation through activating Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Our studies showed that SHP2 knockdown effectively delayed cartilage destruction and reduced osteophyte formation in the mouse model of OA induced by destabilization of the medial meniscus (DMM). Altogether, our study identifies that SHP2 is a novel and potential therapeutic target of OA.
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http://dx.doi.org/10.3389/fcell.2021.646386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063055PMC
April 2021

Two reactive behaviors of chondrocytes in an IL-1β-induced inflammatory environment revealed by the single-cell RNA sequencing.

Aging (Albany NY) 2021 04 20;13(8):11646-11664. Epub 2021 Apr 20.

Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.

Objective: To investigate the heterogeneous responses of expanded chondrocytes, which were cultured in an interleukin (IL)-1β -induced inflammatory environment.

Method: Human articular chondrocytes were expanded, , for 13 days and treated with IL-1β for 0, 24, and 48 h. Cells were collected and subjected to single-cell RNA sequencing. Multiple bioinformatics tools were used to determine the signatures that define chondrocyte physiology.

Results: Two major cell clusters with distinct expression patterns were identified at the initial phase and were with heterogeneous variation that coincides with inflammation progress. They transformed into two terminal cell clusters one of which exhibited OA-phenotype and proinflammatory characteristics through two paths, "response-to-inflammation" and "atypical response-to-inflammation", respectively. The involved cell clusters exhibited intrinsic relationship with cell types within native cartilage from OA patients. Genes controlling cell transformation to OA-phenotype were relating to the tumor necrosis factor (TNF) signaling pathway via NFKB, up-regulated KRAS signaling and the IL2/STAT5 signaling pathway and pathways relating to apoptosis and reactive oxygen species.

Conclusion: The expanded chondrocytes under IL-1β-induced inflammatory progression behave heterogeneously. One of the initial cell clusters could transform into a proinflammatory subpopulation through a termed response-to-inflammation path, which may serve as the core target to alleviate OA progression.
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http://dx.doi.org/10.18632/aging.202857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109072PMC
April 2021

Pristimerin Suppresses RANKL-Induced Osteoclastogenesis and Ameliorates Ovariectomy-Induced Bone Loss.

Front Pharmacol 2020 15;11:621110. Epub 2021 Jan 15.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Osteoporosis is characterized by bone loss and destruction of trabecular architecture, which greatly increases the burden on the healthcare system. Excessive activation of osteoclasts is an important cause of osteoporosis, and suppression of osteoclastogenesis is helpful for the treatment of osteoporosis. Pristimerin, a natural compound, possesses numerous pharmacological effects via inactivating the NF-κB and MAPK pathways, which are closely related to osteoclastogenesis process. However, the relationship between Pristimerin and osteoclastogenesis requires further investigation. In this research, we examined the effect of Pristimerin on osteoclastogenesis and investigated the related mechanisms. Our results showed Pristimerin inhibited RANKL-induced osteoclast differentiation and osteoclastic bone resorption , with decreased expression of osteoclastogenesis-related markers including c-Fos, NFATc1, TRAP, Cathepsin K, and MMP-9 at both mRNA and protein levels. Furthermore, Pristimerin suppressed NF-κB and MAPK signaling pathways, reduced reactive oxygen species (ROS) production and activated the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling during osteoclastogenesis. Our experiments showed that Pristimerin remarkably ameliorated ovariectomy-induced bone loss, reduced serum levels of TNF-α, IL-1β, IL-6, and RANKL, and increased serum level of osteoprotegerin (OPG). Therefore, our research indicated that Pristimerin is a potential chemical for the treatment of osteoporosis.
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http://dx.doi.org/10.3389/fphar.2020.621110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898668PMC
January 2021

Sprayable hydrogel dressing accelerates wound healing with combined reactive oxygen species-scavenging and antibacterial abilities.

Acta Biomater 2021 04 6;124:219-232. Epub 2021 Feb 6.

Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address:

Wound management poses a considerable economic burden on the global healthcare system, considering the impacts of wound infection, delayed healing and scar formation. To this end, multifunctional dressings based on hydrogels have been developed to stimulate skin healing. Herein, we describe the design, fabrication, and characterization of a sprayable hydrogel-based wound dressing loaded with cerium oxide nanoparticles (CeONs) and an antimicrobial peptide (AMP), for combined reactive oxygen species (ROS)-scavenging and antibacterial properties. We adopted a mussel-inspired strategy to chemically conjugate gelatin with dopamine motifs and prepared a hydrogel dressing with improved binding affinity to wet skin surfaces. Additionally, the release of AMP from the hydrogel demonstrated rapid release ablation and contact ablation against four representative bacterial strains, confirming the desired antimicrobial activities. Moreover, the CeONs-loaded hydrogel dressing exhibited favorable ROS-scavenging abilities. The biocompatibility of the multifunctional hydrogel dressing was further proven in vitro by culturing with HaCaT cells. Overall, the benefits of the developed hydrogel wound dressing, including sprayability, adhesiveness, antimicrobial activity, as well as ROS-scavenging and skin-remodeling ability, highlight its promissing translational potentials in wound management. STATEMENT OF SIGNIFICANCE: Various hydrogel-based wound-dressing materials have been developed to stimulate wound healing. However, from the clinical perspective, few of the current wound dressings meet all the intended multifunctional requirements of preventing infection, promoting rapid wound closure, and minimizing scar formation, while simultaneously offering the convenience of application. In the current study, we adopted a mussel-inspired strategy to functionalize the GelMA hydrogels with DOPA to fabricate GelMA-DOPA hydrogel which exhibited an enhanced binding affinity for wound surfaces, AMP HHC-36 and CeONs are further encapsulated into the GelMA-DOPA hydrogel to confer the hydrogel wound dressing with antimicrobial and ROS-scavenging abilities. The GelMA-DOPA-AMP-CeONs dressing offered the benefits of sprayability, adhesiveness, antimicrobial activity, as well as ROS-scavenging and skin-remodeling ability, which might address the therapeutic and economic burdens associated with chronic wound treatment and management.
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http://dx.doi.org/10.1016/j.actbio.2021.02.002DOI Listing
April 2021

Improved Immunoregulation of Ultra-Low-Dose Silver Nanoparticle-Loaded TiO Nanotubes via M2 Macrophage Polarization by Regulating GLUT1 and Autophagy.

Int J Nanomedicine 2020 24;15:2011-2026. Epub 2020 Mar 24.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.

Introduction: The bone regeneration of endosseous implanted biomaterials is often impaired by the host immune response, especially macrophage-related inflammation which plays an important role in the bone healing process. Thus, it is a promising strategy to design an osteo-immunomodulatory biomaterial to take advantage of the macrophage-related immune response and improve the osseointegration performance of the implant.

Methods: In this study, we developed an antibacterial silver nanoparticle-loaded TiO nanotubes ([email protected]) using an electrochemical anodization method to make the surface modification and investigated the influences of [email protected] on the macrophage polarization, osteo-immune microenvironment as well as its potential molecular mechanisms in vitro and in vivo.

Results: The results showed that [email protected] with controlled releasing of ultra-low-dose Ag ions had the excellent ability to induce the macrophage polarization towards the M2 phenotype and create a suitable osteo-immune microenvironment in vitro, via inhibiting PI3K/Akt, suppressing the downstream effector GLUT1, and activating autophagy. Moreover, [email protected] surface could improve bone formation, suppress inflammation, and promote osteo-immune microenvironment compared to the TiO-NTs and polished Ti surfaces in vivo. These findings suggested that [email protected] with controlled releasing of ultra-low-dose Ag ions could not only inhibit the inflammation process but also promote the bone healing by inducing healing-associated M2 polarization.

Discussion: Using this surface modification strategy to modulate the macrophage-related immune response, rather than prevent the host response, maybe a promising strategy for implant surgeries in the future.
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http://dx.doi.org/10.2147/IJN.S242919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102919PMC
July 2020

Enhanced performance of vertical-structured InGaN micro-pixelated light-emitting-diode array fabricated using an ion implantation process.

Opt Lett 2019 Sep;44(18):4562-4565

In this Letter, a new approach to fabricating a high-efficiency vertical-structured InGaN micro-pixelated light-emitting diode (μVLED) is presented. The high-resistivity selective areas are intentionally created in the n-GaN layer through a fluorine (F) ion-implantation process and then used as the electrical isolation regions for realizing a μVLED array consisting of 25×25 pixels with a diameter of 10 μm. The results prove that the dual-energy F ion implantations not only can improve the uniformity of carrier distribution but also can effectively prevent current from leaking along the etched sidewalls, which in turn realize a more efficient carrier injection into the mesa area. More notably, the current-handling capability and corresponding optical output power density of the μVLED array are substantially higher than those of conventional vertical-structured broad-area LEDs. A measured output light power density of the F ion-implanted μVLED array reaches a maximum value of 43  W cm at 3.06  kA cm, before power saturation. The improved luminescence performances of the μVLED array can be attributed to an effective ion-induced heat relaxation and associated lower junction temperature.
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http://dx.doi.org/10.1364/OL.44.004562DOI Listing
September 2019

Long-lasting bactericidal activity through selective physical puncture and controlled ions release of polydopamine and silver nanoparticles-loaded TiO nanorods in vitro and in vivo.

Int J Nanomedicine 2019 24;14:2903-2914. Epub 2019 Apr 24.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.

Titanium (Ti) implant-associated infection, which is mostly caused by bacterial adhesion and biofilm formation, may result in implant failure and secondary surgery. Thus it is an urgent issue to prevent bacterial infections at the earliest step. To develop a novel surface strategy of polydopamine (PDA) and silver (Ag) nanoparticle-loaded TiO nanorods (NRDs) coatings on Ti alloy. [email protected] NRDs was fabricated on Ti alloy by hydrothermal synthesis. The antibacterial activity of [email protected] NRDs against and methicillin-resistant were tested by FE-SEM, Live/Dead staining, zone of inhibition, bacteria counting method and protein leakage analysis . In addition, an implant infection model was conducted and the samples were tested by X-ray, Micro-CT and histological analysis . Besides, cell morphology and cytotoxicity of Mouse calvarial cells (MC3T3-E1) were characterized by FE-SEM, immunofluorescence and CCK-8 test . Our study successfully developed a new surface coating of [email protected] NRDs. The selective physical puncture of bacteria and controlled release of Ag+ ions of [email protected] NRDs achieved a long-lasting bactericidal ability and anti-biofilm activity with satisfied biocompatibility. This strategy may be promising for clinical applications to reduce the occurrence of infection in the implant surgeries.
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http://dx.doi.org/10.2147/IJN.S202625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497113PMC
July 2019

Poly(dopamine) and Ag nanoparticle-loaded TiO nanotubes with optimized antibacterial and ROS-scavenging bioactivities.

Nanomedicine (Lond) 2019 Apr 14;14(7):803-818. Epub 2019 Jan 14.

Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, PR China.

Aim: To create polydopamine (PDA) and Ag nanoparticle-loaded TiO nanotubes coating on titanium (Ti) alloy.

Materials & Methods: TiO-PDA-Ag coating was fabricated on Ti implants by electrochemical anodization. The in vitro and in vivo bactericidal and antibiofilm activities were tested. Intracellular reactive oxygen species (ROS) and antioxidative capability were measured, and cell proliferation, adhesion and cell morphology were characterized.

Results: TiO-PDA-Ag coating showed satisfactory bactericidal and antibiofilm activities in vitro and in vivo, improved Ag release pattern, evident ROS scavenging properties and enhanced cell adhesion and proliferation.

Conclusion: Our study successfully fabricated a PDA and Ag nanoparticle-loaded TiO nanotubes coating on Ti alloy. The improved Ag release kinetics and ROS-scavenging properties achieve an optimal balance between antibacterial ability and biocompatibility.
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http://dx.doi.org/10.2217/nnm-2018-0131DOI Listing
April 2019

Silver-loaded nanotubular structures enhanced bactericidal efficiency of antibiotics with synergistic effect in vitro and in vivo.

Int J Nanomedicine 2017 27;12:731-743. Epub 2017 Jan 27.

Orthopaedic Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.

Antibiotic-resistant bacteria have become a major issue due to the long-term use and abuse of antibiotics in treatments in clinics. The combination therapy of antibiotics and silver (Ag) nanoparticles is an effective way of both enhancing the antibacterial effect and decreasing the usage of antibiotics. Although the method has been proved to be effective in vitro, no in vivo tests have been carried out at present. Herein, we described a combination therapy of local delivery of Ag and systemic antibiotics treatment in vitro in an infection model of rat. Ag nanoparticle-loaded TiO nanotube (NT) arrays (Ag-NTs) were fabricated on titanium implants for a customized release of Ag ion. The antibacterial properties of silver combined with antibiotics vancomycin, rifampin, gentamicin, and levofloxacin, respectively, were tested in vitro by minimum inhibitory concentration (MIC) assay, disk diffusion assay, and antibiofilm formation test. Enhanced antibacterial activity of combination therapy was observed for all the chosen bacterial strains, including gram-negative (ATCC 25922), gram-positive (ATCC 25923), and methicillin-resistant (MRSA; ATCC 33591 and ATCC 43300). Moreover, after a relative short (3 weeks) combinational treatment, animal experiments in vivo further proved the synergistic antibacterial effect by X-ray and histological and immunohistochemical analyses. These results demonstrated that the combination of Ag nanoparticles and antibiotics significantly enhanced the antibacterial effect both in vitro and in vivo through the synergistic effect. The strategy is promising for clinical application to reduce the usage of antibiotics and shorten the administration time of implant-associated infection.
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http://dx.doi.org/10.2147/IJN.S123648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291465PMC
April 2017

Blockade of the human ether-a-go-go-related gene potassium channel by ketamine.

J Pharm Pharmacol 2013 Sep 10;65(9):1321-8. Epub 2013 Jul 10.

Cardio-Electrophysiological Research Laboratory, Medical College, Wuhan University of Science and Technology, Wuhan, China.

Objectives: The inhibition of the cardiac rapid delayed rectifier potassium current (IKr ) and its cloned equivalent human ether-a-go-go-related gene (hERG) channel illustrate QT interval prolonging effects of a wide range of clinically used drugs. In this study, the direct interaction of the intravenous anaesthetic ketamine with wild-type (WT) and mutation hERG currents (IhERG ) was investigated.

Methods: The hERG channel (WT, Y652A and F656A) was expressed in Xenopus oocytes and studied using standard two-microelectrode voltage-clamp techniques.

Key Findings: WT hERG is blocked in a concentration-dependent manner with IC50  = 12.05 ± 1.38 μm by ketamine, and the steady-state inactivation curves are shifted to more negative potentials (about -27 mV). The mutation to Ala of Y652 and F656 located on the S6 domain attenuate IhERG blockade by ketamine, and produced approximately 9-fold and 2.5-fold increases in IC50 compared with that of WT hERG channel, respectively.

Conclusions: Ketamine blocks WT IhERG expressed in Xenopus oocytes in a concentration-dependent manner and predominantly interacts with the open hERG channels. The interaction of ketamine with hERG channel may involve the aromatic residues Tyr652 and Phe656.
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http://dx.doi.org/10.1111/jphp.12095DOI Listing
September 2013