Publications by authors named "Qihui Zhou"

54 Publications

Nanoparticles for Oral Cancer Diagnosis and Therapy.

Bioinorg Chem Appl 2021 23;2021:9977131. Epub 2021 Apr 23.

Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.

Oral cancer is the sixth most common malignant cancer, affecting the health of people with an unacceptably high mortality rate. Despite numerous clinical methods in the diagnosis and therapy of oral cancer (e.g., magnetic resonance imaging, computed tomography, surgery, and chemoradiotherapy), they still remain far from optimal. Therefore, an urgent need exists for effective and practical techniques of early diagnosis and effective therapy of oral cancer. Currently, various types of nanoparticles have aroused wide public concern, representing a promising tool for diagnostic probes and therapeutic devices. Their inherent physicochemical features, including ultrasmall size, high reactivity, and tunable surface modification, enable them to overcome some of the limitations and achieve the expected diagnostic and therapeutic effect. In this review, we introduce different types of nanoparticles that emerged for the diagnosis and therapy of oral cancers. Then, the challenges and future perspectives for nanoparticles applied in oral cancer diagnosis and therapy are presented. The objective of this review is to help researchers better understand the effect of nanoparticles on oral cancer diagnosis and therapy and may accelerate breakthroughs in this field.
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http://dx.doi.org/10.1155/2021/9977131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088384PMC
April 2021

Hierarchically hybrid biocoatings on Ti implants for enhanced antibacterial activity and osteogenesis.

Colloids Surf B Biointerfaces 2021 Apr 29;204:111802. Epub 2021 Apr 29.

Department of Orthodontics, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China; School of Stomatology, Qingdao University, Qingdao, 266003, China; Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China. Electronic address:

Titanium (Ti) is widely applied as bone-anchoring implants in dental and orthopedic applications owing to its superior mechanical characteristics, high corrosion resistance, and excellent biocompatibility. Nevertheless, Ti-based implants with the deficiencies of insufficient osteoinduction and associated infections can result in implant failure, which significantly limits its applications in some cases. In this work, hierarchically hybrid biocoatings on Ti implants are developed by gradual incorporation of polydopamine (PDA), ZnO nanoparticles (nZnO), and chitosan (CS)/nanocrystal hydroxyapatite (nHA) via oxidative self-polymerization, nanoparticle deposition, solvent casting and evaporation methods for enhancing their antibacterial activity and osteogenesis. The modification of PDA on porous reticular Ti substrates greatly reduces the surface roughness, wettability, protein adsorption, and provides high adhesion to the deposited nZnO. Further, incorporating nZnO on PDA-coated Ti surfaces affects the surface structure and wettability, significantly inhibits the growth of both Staphylococcus aureus and Escherichia coli. Moreover, the CS/nHA-doped coating on the nZnO-modified Ti surfaces remarkably improves cytocompatibility and enhances the osteogenic differentiation of MC3T3-E1 cells by upregulating the protein expression of alkaline phosphatase. This work offers a promising alternative for developing Ti implants with long-lifetime bioactivity to achieve strong antibacterial ability and enhanced bone formation for potential dental/orthopedic applications.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111802DOI Listing
April 2021

Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus.

Gut Pathog 2021 Apr 12;13(1):22. Epub 2021 Apr 12.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.

Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Of the medications currently available, only IFN-α can potentially target cccDNA. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.
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http://dx.doi.org/10.1186/s13099-021-00421-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040234PMC
April 2021

Enhanced Eradication of Bacterial/Fungi Biofilms by Glucose Oxidase-Modified Magnetic Nanoparticles as a Potential Treatment for Persistent Endodontic Infections.

ACS Appl Mater Interfaces 2021 Apr 7;13(15):17289-17299. Epub 2021 Apr 7.

Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.

Bacterial/fungal biofilm-mediated persistent endodontic infections (PEIs) are one of the most frequent clinical lesions in the oral cavity, resulting in apical periodontitis and tooth damage caused by loss of minerals. The conventional root canal disinfectants are poorly bio-safe and harmful to teeth and tissues, making them ineffective in treating PEIs. The development of nanomaterials is emerging as a promising strategy to eradicate disease-related bacteria/fungi. Herein, glucose oxidase (GOx)-modified magnetic nanoparticles (MNPs) were synthesized a facile and versatile route for investigating their effects on removing PEI-related bacterial/fungal biofilms. It is found that GOx was successfully immobilized on the MNPs by detecting the changes in the diameter, chemical functional group, charge, and magnetic response. Further, we demonstrate that GOx-modified MNPs (GMNPs) exhibit highly effective antibacterial activity against and . Moreover, the antibacterial/fungal activity of GMNPs is greatly dependent on their concentrations. Importantly, when placed in contact with bacterial/fungal biofilms, the dense biofilm matrix is destructed due to the movement of GMNPs induced by the magnetic field, the formation of reactive oxygen species, and nutrient starvation induced by GOx. Also, the experiment shows that the as-prepared GMNPs have excellent cytocompatibility and blood compatibility. Thus, GMNPs offer a novel strategy to treat bacteria/fungi-associated PEIs for potential clinical applications.
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http://dx.doi.org/10.1021/acsami.1c01748DOI Listing
April 2021

Fucoidan as a marine-origin prebiotic modulates the growth and antibacterial ability of Lactobacillus rhamnosus.

Int J Biol Macromol 2021 Jun 20;180:599-607. Epub 2021 Mar 20.

Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China; School of Stomatology, Qingdao University, Qingdao 266003, China. Electronic address:

Fucoidan has received much attention in healthy food and biomedicine owing to their unique (bio)physicochemical properties, particularly antibacterial and antiviral. Pathogenic microorganisms and probiotics are coexisting in many tissues (e.g., gut, oral, and vagina). However, the effect of fucoidan on probiotics has not been examined. Herein, fucoidan sterilized by different methods (i.e., 0.22 μm filter and high-temperature autoclave) is applied to explore its effect on the responses of Lactobacillus rhamnosus. It is found that high-temperature autoclave treatment causes the depolymerization of fucoidan. Further, the proliferation, morphology, and metabolism of probiotics are greatly dependent on the concentrations of fucoidan. The formation of probiotic biofilm is reduced with an increased concentration of fucoidan. Moreover, the antibacterial ability of probiotics initially increases and then decreases with an increased concentration of fucoidan. Thus, fucoidan could serve as a new marine-origin prebiotic, offering new insight into probiotic modulation and its application in inhibiting bacterial infections.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.03.065DOI Listing
June 2021

High-Throughput Methods in the Discovery and Study of Biomaterials and Materiobiology.

Chem Rev 2021 Apr 11;121(8):4561-4677. Epub 2021 Mar 11.

Institute for Translational Medicine, Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China.

The complex interaction of cells with biomaterials (i.e., materiobiology) plays an increasingly pivotal role in the development of novel implants, biomedical devices, and tissue engineering scaffolds to treat diseases, aid in the restoration of bodily functions, construct healthy tissues, or regenerate diseased ones. However, the conventional approaches are incapable of screening the huge amount of potential material parameter combinations to identify the optimal cell responses and involve a combination of serendipity and many series of trial-and-error experiments. For advanced tissue engineering and regenerative medicine, highly efficient and complex bioanalysis platforms are expected to explore the complex interaction of cells with biomaterials using combinatorial approaches that offer desired complex microenvironments during healing, development, and homeostasis. In this review, we first introduce materiobiology and its high-throughput screening (HTS). Then we present an in-depth of the recent progress of 2D/3D HTS platforms (i.e., gradient and microarray) in the principle, preparation, screening for materiobiology, and combination with other advanced technologies. The Compendium for Biomaterial Transcriptomics and high content imaging, computational simulations, and their translation toward commercial and clinical uses are highlighted. In the final section, current challenges and future perspectives are discussed. High-throughput experimentation within the field of materiobiology enables the elucidation of the relationships between biomaterial properties and biological behavior and thereby serves as a potential tool for accelerating the development of high-performance biomaterials.
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http://dx.doi.org/10.1021/acs.chemrev.0c00752DOI Listing
April 2021

A narrative review of the roles of indoleamine 2,3-dioxygenase and tryptophan-2,3-dioxygenase in liver diseases.

Ann Transl Med 2021 Jan;9(2):174

Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are induced by several immune factors, such as interferon-γ, and act as intracellular enzymes that catabolize essential amino acid tryptophan into kynurenine and other downstream metabolites, including kynurenic acid (KYNA), xanthurenic acid (XA) and so on. IDO and TDO work as a double-edge sword. On one hand, they exert the immunomodulatory effects, especially immunosuppressive effects on the microenvironment including infections, pregnancy, tumor cells escape and transplantation. TDO plays the major role under basal conditions, while IDO comes into play under different circumstances of immune activation, thus IDO has a wider spectrum of immune regulation. On the other hand, these enzymes also inhibit pathogens such as Chlamydia pneumoniae, Staphylococcus aureus, Toxoplasma gondii and so on. Moreover, IDO regulates metabolic health through shaping intestinal microbiota. Recently, these enzymes have attracted more and more attention in liver diseases. Several studies have indicated that IDO and TDO can modulate viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, liver cancer even liver transplantation. Targeting them or their antagonists may provide novel therapeutic treatments for liver diseases. In this review, we will discuss the exact roles that IDO and TDO play in diverse hepatic diseases.
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http://dx.doi.org/10.21037/atm-20-3594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867903PMC
January 2021

Comparative proteomic analysis reveals insights into the dynamic responses of maize (Zea mays L.) to Setosphaeria turcica infection.

Plant Sci 2021 Mar 6;304:110811. Epub 2021 Jan 6.

State Key Laboratory of North China Crop Improvement and Regulation, Baoding, China; College of Life Sciences, Hebei Agricultural University, Baoding, Hebei, 071001, China; Key Laboratory of Hebei Province for Plant Physiology and Molecular Pathology, Hebei, 071001, China. Electronic address:

Maize (Zea mays L.) production is severely affected by northern corn leaf blight (NCLB), which is a destructive foliar disease caused by Setosphaeria turcica. In recent years, studies on the interaction between maize and S. turcica have been focused at the transcription level, with no research yet at the protein level. Here, we applied tandem mass tag labelling and liquid chromatography-tandem mass spectrometry to investigate the proteomes of maize leaves at 24 h and 72 h post-inoculation (hpi) with S. turcica. In total, 4740 proteins encoded by 4711 genes were quantified in this study. Clustering analyses provided an understanding of the dynamic reprogramming of leaves proteomes by revealing the functions of different proteins during S. turcica infection. Screening and classification of differentially expressed proteins (DEPs) revealed that numerous defense-related proteins, including defense marker proteins and proteins related to the phenylpropanoid lignin biosynthesis, benzoxazine biosynthesis and the jasmonic acid signalling pathway, participated in the defense responses of maize to S. turcica infection. Furthermore, the earlier induction of GST family proteins contributed to the resistance to S. turcica. In addition, the protein-protein interaction network of DEPs suggests that some defense-related proteins, for example, ZmGEB1, a hub node, play key roles in defense responses against S. turcica infection. Our study findings provide insight into the complex responses triggered by S. turcica at the protein level and lay the foundation for studying the interaction process between maize and S. turcica infection.
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http://dx.doi.org/10.1016/j.plantsci.2020.110811DOI Listing
March 2021

Catalytic hairpin assembly indirectly covalent on FeO@C nanoparticles with signal amplification for intracellular detection of miRNA.

Talanta 2021 Feb 28;223(Pt 1):121675. Epub 2020 Sep 28.

Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education, China), School of Environmental Science and Technology, Dalian University of Technology, Dalian, 116024, China. Electronic address:

Fluorescence resonance energy transfer, a promising method for in situ imaging of miRNA in living cells, has intrinsic limitation on sensitivity and selectivity. Herein, a fluorescent amplification strategy based on catalyzed hairpin assembly indirectly covalent on FeO@C nanoparticles via short single-stranded DNA was investigated for cellular miRNA detection in living cells, integrating non-enzyme target-active releasing for amplifying the signal output, highly quenching efficiency of FeO@C nanoparticles with low background, ssDNA assisted fluorescent group-fueled chain releasing from FeO@C nanoparticles with enhanced fluorescence response. The designed platform exhibits highly sensitive in a wide linear concentration range of 0.450 pM-190 pM and is highly specific for miRNA-20a detection with the ability of discriminating one mistake base. Additionally, the CHA-FeO@C was successfully applied in imaging visualization of miRNA-20a in the living cell. The strategy provides a promising bioassay approach for clinical research.
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http://dx.doi.org/10.1016/j.talanta.2020.121675DOI Listing
February 2021

A biodegradable antibacterial alginate/carboxymethyl chitosan/Kangfuxin sponges for promoting blood coagulation and full-thickness wound healing.

Int J Biol Macromol 2021 Jan 28;167:182-192. Epub 2020 Nov 28.

Institute for Translational Medicine, Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China; School of Stomatology, Qingdao University, Qingdao 266003, China. Electronic address:

Conventional wound-dressing materials with structural and functional deficiencies are not effective in promoting wound healing. The development of multifunctional wound dressings is emerging as a promising strategy to accelerate blood coagulation, inhibit bacterial infection, and trigger full-thickness wound into a regenerative process. Herein, multifunctional composite sponges were developed by incorporation of traditional Chinese medicine Kangfuxin (KFX) into alginate (AG)/carboxymethyl chitosan (CMC) via green crosslinking, electrostatic interaction, and freeze-drying methods. It is demonstrated that the AG/CMC/KFX (ACK) sponges exhibit a highly interconnected and porous structure, suitable water vapor transmittance, excellent elastic properties, antibacterial behavior, cytocompatibility, and rapid hemostasis. Further, in a rat full-thickness wounds model, the ACK sponge containing 10% KFX (ACK-10) significantly facilitates wound closure compared to the AC group and ACK sponge containing 5% and 15% KFX. Thus, the multifunctional ACK-10 composite sponge has great promise for the application of full-thickness wound healing.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.11.168DOI Listing
January 2021

Light-induced molecular rotation triggers on-demand release from liposomes.

Chem Commun (Camb) 2020 Aug 3;56(62):8774-8777. Epub 2020 Jul 3.

University of Groningen, University Medical Center Groningen, Department of Biomedical Engineering, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Controllable molecular release from delivery vehicles is essential to successfully reduce drug toxicity and improve therapeutic efficacy. Light-powered hydrophobic molecular motors were therefore incorporated in liposomes to use molecular rotation to facilitate on-demand release. The extent of the release was precisely controlled by irradiation times, providing a simple yet sophisticated responsive molecular nanocarrier.
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http://dx.doi.org/10.1039/d0cc02499fDOI Listing
August 2020

Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS.

Acta Neuropathol 2020 08 19;140(2):121-142. Epub 2020 Jun 19.

German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany.

Expansion of a (GC) repeat in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To directly compare these in vivo, we created congenic poly-GA and poly-PR mice. 40% of poly-PR mice were affected with ataxia and seizures, requiring euthanasia by 6 weeks of age. The remaining poly-PR mice were asymptomatic at 14 months of age, likely due to an 80% reduction of the transgene mRNA in this subgroup. In contrast, all poly-GA mice showed selective neuron loss, inflammation, as well as muscle denervation and wasting requiring euthanasia before 7 weeks of age. In-depth analysis of peripheral organs and blood samples suggests that peripheral organ failure does not drive these phenotypes. Although transgene mRNA levels were similar between poly-GA and affected poly-PR mice, poly-GA aggregated far more abundantly than poly-PR in the CNS and was also found in skeletal muscle. In addition, TDP-43 and other disease-linked RNA-binding proteins co-aggregated in rare nuclear inclusions in the hippocampus and frontal cortex only in poly-GA mice. Transcriptome analysis revealed activation of an interferon-responsive pro-inflammatory microglial signature in end-stage poly-GA but not poly-PR mice. This signature was also found in all ALS patients and enriched in C9orf72 cases. In summary, our rigorous comparison of poly-GA and poly-PR toxicity in vivo indicates that poly-GA, but not poly-PR at the same mRNA expression level, promotes interferon responses in C9orf72 disease and contributes to TDP-43 abnormalities and neuron loss selectively in disease-relevant regions.
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http://dx.doi.org/10.1007/s00401-020-02176-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360660PMC
August 2020

Reactive Oxygen Species-Related Nanoparticle Toxicity in the Biomedical Field.

Nanoscale Res Lett 2020 May 20;15(1):115. Epub 2020 May 20.

Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China.

The unique physicochemical characteristics of nanoparticles have recently gained increasing attention in a diverse set of applications, particularly in the biomedical field. However, concerns about the potential toxicological effects of nanoparticles remain, as they have a higher tendency to generate excessive amounts of reactive oxygen species (ROS). Due to the strong oxidation potential, the excess ROS induced by nanoparticles can result in the damage of biomolecules and organelle structures and lead to protein oxidative carbonylation, lipid peroxidation, DNA/RNA breakage, and membrane structure destruction, which further cause necrosis, apoptosis, or even mutagenesis. This review aims to give a summary of the mechanisms and responsible for ROS generation by nanoparticles at the cellular level and provide insights into the mechanics of ROS-mediated biotoxicity. We summarize the literature on nanoparticle toxicity and suggest strategies to optimize nanoparticles for biomedical applications.
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http://dx.doi.org/10.1186/s11671-020-03344-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239959PMC
May 2020

Role of Circular RNAs in the Pathogenesis of Cardiovascular Disease.

J Cardiovasc Transl Res 2020 08 12;13(4):572-583. Epub 2020 May 12.

Institute for Translational Medicine, Qingdao University, Qingdao, 266021, China.

Circular RNAs (circRNAs) are single-strand covalently closed circular noncoding RNAs that are endogenous transcripts generated from linear precursor mRNA through a backsplicing mechanism. With the development of high-throughput sequencing technology, a number of circRNAs have been identified and proved to play key roles in various pathophysiological processes, such as metabolic diseases, cancers, and cardiovascular diseases. An increasing number of studies have shown that circRNAs are widely expressed in cardiac tissues and play important roles in the development of multiple cardiovascular diseases. Here, we review the current understanding of circRNA biogenesis and functions and the roles of circRNAs in cardiovascular diseases. We also highlight the molecular mechanisms underlying the role of circRNAs in the pathogenesis of cardiovascular diseases. A better understanding of the biological function of circRNAs in cardiovascular diseases will be helpful for the development of effective biomarkers for the diagnosis and treatment of these diseases.
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http://dx.doi.org/10.1007/s12265-019-09912-2DOI Listing
August 2020

Epstein-Barr virus associated hepatic smooth muscle tumor in a patient with acquired immunodeficiency syndrome: A case report.

Medicine (Baltimore) 2020 May;99(18):e19930

Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Introduction: Epstein-Barr virus (EBV) associated smooth muscle tumors (SMTs) usually present under the condition of immunosuppression, including congenital immunodeficiency syndrome-SMT, post-transplantation-SMT and HIV-SMT. HIV-SMTs are most likely to invade the central nervous system, followed by the liver, lungs, and other locations. Many laboratory techniques, including serological techniques, polymerase chain reaction and immunohistochemistry (IHC), are employed to determine the aetiologies of these tumours. With respect to therapy, surgical resection is the main treatment. In patients with immunodeficiency, improving immune status is significant for defending against other viruses. We describe a case of the primary focus of SMT in the liver of HIV-positive patient without any metastasis.

Patient Concerns: A young male HIV-positive patient complained of fever and abdominal pain for 2 months.

Diagnosis: IHC of liver tissue confirmed the finding: EBV-related smooth muscle tumor.

Interventions: Given the patient's general condition, he was not a suitable candidate for surgical resection. He was given antibiotics, antifungal agents and EBV-directed agents to control infection as well as highly active antiretroviral therapy to enhance the immunity.

Outcomes: The patient's symptoms improved. He was discharged.

Conclusions: In conclusion, EBV-related HIV-SMTs is a rare neoplasm found in the liver among immunodeficient patients. This case highlights that a variety of examinations such as IHC for smooth muscle markers (smooth muscle actin and desmin) and EBER, as well as polymerase chain reaction for EBV DNA should be done when diagnoses are ambiguous.
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http://dx.doi.org/10.1097/MD.0000000000019930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440249PMC
May 2020

Dihydrotanshinone I Attenuates Plaque Vulnerability in Apolipoprotein E-Deficient Mice: Role of Receptor-Interacting Protein 3.

Antioxid Redox Signal 2021 02 4;34(5):351-363. Epub 2020 Jun 4.

Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi, China.

Vulnerable plaque disruption in advanced atherosclerosis leads to acute thrombus and subsequent myocardial infarction and severely threatens human health. Necroptosis of macrophage involved in the necrotic core is one key factor for plaque vulnerability. Dihydrotanshinone I (DHT) is a natural diterpenoid isolated from Danshen demonstrating effective anti-inflammatory property. It is accepted that inflammation plays a crucial role in the process of atherogenesis. However, whether DHT prevents atherosclerosis is poorly understood. Here, we investigated the effect of DHT on vulnerable plaque in an apolipoprotein E-deficient (ApoE) mice model of atherosclerosis and the underlying protective mechanisms. In the experiment, first LPS/ZVAD (LPS, lipopolysaccharide; ZVAD, ZVAD-FMK, a cell-permeable pan-caspase inhibitor) stimulated necroptosis of macrophage in a receptor-interacting protein 3 (RIP3)-dependent pathway, which was regulated by Toll-like receptor 4 (TLR4) dimerization. Further study illustrated that activated RIP3 evoked endoplasmic reticulum stress as well as reactive oxygen species generation. Both DHT and RIP3 silence reversed the above phenomena. In the experiment, aorta and serum samples were collected to determine features of plaque stability, including plaque size, necrotic core area, as well as collagen content in fibrous cap and the expression of related protein molecules. Both DHT and RIP3 inhibitor GSK872 significantly enhanced plaque stability in ApoE mice by reducing oxidative stress, shrinking necrotic core area, increasing collagen content, and decreasing RIP3 expression. Our study showed that DHT may stabilize vulnerable plaque by suppressing RIP3-mediated necroptosis of macrophage, which indicates its potential application as a lead compound for cardiovascular treatments, especially for advanced atherosclerosis. 34, 351-363.
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http://dx.doi.org/10.1089/ars.2019.7796DOI Listing
February 2021

Well Plate Integrated Topography Gradient Screening Technology for Studying Cell-Surface Topography Interactions.

Adv Biosyst 2020 01 4;4(1):e1900218. Epub 2019 Nov 4.

W.J. Kolff Institute for Biomedical Engineering and Materials Science Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, the Netherlands.

New high-throughput technologies for cell-material interaction studies provide researchers with powerful tools to speed up research in the field of biomaterial-cell interactions. However, sharing technologies is often difficult due to the necessity of specific knowledge and experiences. Engineered surfaces can elucidate effects of surface topography on cell behavior, which is of critical value for gaining control over cellular processes. Here, the translation of a gradient-based high-throughput cell screening approach for aligned nano/micro topographies interacting with cells is presented. An aligned topography 96-well plate is created by upscaling of highly specific gradient technology. The resulting cell culture dishes are compatible with general laboratory and imaging equipment, and the platform allows for studying cell behavior with regard to adhesion and alignment. The challenge lies in increasing the dimensions of the previous 1 × 1 cm gradient topography substrate, to be able to cover the span of a 96-well plate and translate it into a standardized cell-screening tool. Adhesion experiments of human bone marrow derived mesenchymal stem cells confirm the standardization, compatibility, and usability of the technology. In the process of using multi-system imaging and analysis, it becomes apparent that future challenges need to include universally applied data analysis approaches.
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http://dx.doi.org/10.1002/adbi.201900218DOI Listing
January 2020

Biointerface topography regulates phenotypic switching and cell apoptosis in vascular smooth muscle cells.

Biochem Biophys Res Commun 2020 06 8;526(3):841-847. Epub 2020 Apr 8.

Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China. Electronic address:

Background: In-stent restenosis (ISR) is a complex disease that occurs after coronary stenting procedures. The development of quality materials and improvement of our understanding on significant factors regulating ISR are essential for enhancing prognosis. Vascular smooth muscle cells (VSMCs) are the main constituent cells of blood vessel walls, and dysfunction of VMSCs can exacerbate ISR. Accordingly, in this study, we explored the influence of wrinkled material topography on the biological functions of VSMCs.

Methods: Polydimethylsiloxane with a wrinkled topography was synthesized using elastomer base and crosslinking and observed by atomic force microscopy. VSMC proliferation, apoptosis, and morphology were determined by Cell Counting Kit-8 assays, fluorescence-assisted cell sorting, and phalloidin staining. α-Smooth muscle actin (α-SMA), major histocompatibility complex (MHC), and calponin 1 (CNN-1) expression levels were measured by quantitative real-time polymerase chain reaction and western blotting. Moreover, p53 and cleaved caspase-3 expression levels were evaluated by western blotting in VSMCs to assess apoptotic induction.

Results: Surface topographies were not associated with a clear orientation or elongation of VSMCs. The number of cells was increased on wrinkled surfaces (0.7 μm in amplitude, and 3 μm in wavelength [W3]) compared with that on other surfaces, contributing to continuously increased cell proliferation. Moreover, interactions of VSMCs with the W3 surface suppressed phenotypic switching, resulting in ISR via regulation of α-SMA, calponin-1, and SM-MHC expression. The surface with an amplitude of 0.05 μm and a wavelength of 0.5 μm (W0.5) promoted apoptosis by inducing caspase 3 and p53 activities.

Conclusion: Introduction of aligned topographies on biomaterial scaffolds could provide physical cues to modulate VSMC responses for engineering vascular constructs. Materials with wrinkled topographies could have applications in the development of stents to reduce ISR.
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http://dx.doi.org/10.1016/j.bbrc.2020.03.038DOI Listing
June 2020

Topography induced stiffness alteration of stem cells influences osteogenic differentiation.

Biomater Sci 2020 May 5;8(9):2638-2652. Epub 2020 Apr 5.

Department of Biomedical Engineering-FB40, University of Groningen, University Medical Center Groningen, Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Topography-driven alterations in cell morphology tremendously influence cell biological processes, particularly stem cell differentiation. Aligned topography is known to alter the cell shape, which we anticipated to also induce altered physical properties of the cell. Here, we show that topography has a significant influence on single cell stiffness of human bone marrow derived-Mesenchymal Stem Cells (hBM-MSCs) and the osteogenic differentiation of these. Aligned topographies were used to control the cell elongation, depicted as the cell aspect ratio (C). Intriguingly, an equal C elicited from different topographies, resulted in highly altered differentiation behavior and the underlying single cell mechanics was found to be critical. The cell behavior was found to be focal adhesion-mediated and induced stiffness alterations rather than just influencing the cell elongation. The effect was further corroborated by investigations of the transcriptional regulators YAP. Our study provides insight into how mechanical properties of the cell, which are stimulated by topography, modulate the osteogenesis of hBM-MSCs, which is beneficial for improving the understanding of interactions between stem cells and topography for developing applications of tissue engineering and regenerative medicine.
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http://dx.doi.org/10.1039/d0bm00264jDOI Listing
May 2020

The effect of doxycycline-containing chitosan/carboxymethyl chitosan nanoparticles on NLRP3 inflammasome in periodontal disease.

Carbohydr Polym 2020 Jun 12;237:116163. Epub 2020 Mar 12.

Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China. Electronic address:

A polyelectrolyte complex nanoparticle comprising chitosan (CS) and carboxymethyl chitosan (CMCS) was prepared (CS/CMCS-NPs) by ionic gelation, which was then used as a doxycycline carrier (Dox:CS/CMCS-NPs). The obtained CS/CMCS-NPs and Dox:CS/CMCS-NPs were characterized for various parameters and bacteriostatic ability against Porphyromonas gingivalis. The regulation of related genes and proteins of NLRP3 inflammasome and IL-1β in human gingival fibroblasts (HGFs) was characterized by qRT-PCR, western blotting and ELISA. The results showed that Dox:CS/CMCS-NPs had an orderly morphology and an excellent cytocompatibility. P. gingivalis was strongly inhibited by Dox:CS/CMCS-NPs contrasted with control group. Dox:CS/CMCS-NPs effectively down-regulated both gene and protein levels of NLRP3 inflammasome and IL-1β in HGFs. This study provides a new method for rational application of Dox in the clinical treatment of periodontal disease and a new direction for explaining the mechanism of action of Dox:CS/CMCS-NPs and more drug-carrying nanoparticles.
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http://dx.doi.org/10.1016/j.carbpol.2020.116163DOI Listing
June 2020

Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD.

EMBO J 2020 04 16;39(8):e102811. Epub 2020 Mar 16.

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.
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http://dx.doi.org/10.15252/embj.2019102811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156967PMC
April 2020

Microfabrication of monolithic wafer-level miniaturized millimeter-wave air-filled half-mode waveguide filter based on the inward curving split ring resonator array.

Nanotechnology 2020 May 21;31(19):195202. Epub 2020 Feb 21.

College of Electronic Science and Technology, National University of Defense Technology, Changsha, People's Republic of China. Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Canada.

In this paper, we propose a miniaturized monolithic bandpass filter utilizing an air-filled half-mode waveguide and an inward curving split ring resonator array in the millimeter-wave band. The waveguide blocks the wave below cutoff frequency and the uniplanar array forms a rejection band above the transmission band. The microfabrication process of the filter adopts photoimageable technology and the combination of films with different thicknesses to build a 3D structure. The measured prototype has a center frequency at 65.5 GHz with a 3 dB fractional bandwidth of 30.7%. The minimum insertion loss is 2.1 dB. The proposed component offers excellent performance including a wide transmission band, a low pass-band insertion loss, an excellent isolation in the stop-band, and a steep roll-off at the upper cutoff frequency. Besides, due to the scalability of the waveguide and periodic array, this filter can be adapted for other frequency ranges.
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http://dx.doi.org/10.1088/1361-6528/ab7048DOI Listing
May 2020

Unidirectional rotating molecular motors dynamically interact with adsorbed proteins to direct the fate of mesenchymal stem cells.

Sci Adv 2020 01 29;6(5):eaay2756. Epub 2020 Jan 29.

University of Groningen, University Medical Center Groningen, Department of Biomedical Engineering-FB40, W.J. Kolff Institute for Biomedical Engineering and Materials Science-FB41, A. Deusinglaan 1, 9713 AV Groningen, Netherlands.

Artificial rotary molecular motors convert energy into controlled motion and drive a system out of equilibrium with molecular precision. The molecular motion is harnessed to mediate the adsorbed protein layer and then ultimately to direct the fate of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). When influenced by the rotary motion of light-driven molecular motors grafted on surfaces, the adsorbed protein layer primes hBM-MSCs to differentiate into osteoblasts, while without rotation, multipotency is better maintained. We have shown that the signaling effects of the molecular motion are mediated by the adsorbed cell-instructing protein layer, influencing the focal adhesion-cytoskeleton actin transduction pathway and regulating the protein and gene expression of hBM-MSCs. This unique molecular-based platform paves the way for implementation of dynamic interfaces for stem cell control and provides an opportunity for novel dynamic biomaterial engineering for clinical applications.
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http://dx.doi.org/10.1126/sciadv.aay2756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989133PMC
January 2020

Biological effects on tooth root surface topographies induced by various mechanical treatments.

Colloids Surf B Biointerfaces 2020 Apr 20;188:110748. Epub 2019 Dec 20.

Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China; School of Stomatology of Qingdao University, Qingdao, 266003, China. Electronic address:

The cleaning and physicochemical properties on tooth root biointerfaces are pivotal for periodontal healing. Herein, this work investigated the impact of multi-treatment on the physicochemical features of tooth root surfaces and the responsive behavior of human gingival fibroblasts (hGFs). It was found that the combination of various mechanical treatments significantly affects the topographical pattern and size as well as wettability on tooth root surfaces. Furthermore, biological experiments revealed that hGF behaviors (i.e., cell adhesion, shape, spreading, arrangement, and viability) were regulated by the topography and wettability of tooth root surfaces. Also, there was no significant difference in the protein expression of NLRP3 inflammasome and IL-1β in hGFs among tooth root surfaces under various treatments. This study provides new insights to efficiently remove the dental calculus and to understand the interaction between the tooth root interface and cell, which could guide the clinical operation and thereby is more conducive to periodontal recovery.
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http://dx.doi.org/10.1016/j.colsurfb.2019.110748DOI Listing
April 2020

Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model.

EMBO Mol Med 2020 02 20;12(2):e10919. Epub 2019 Dec 20.

German Center for Neurodegenerative Diseases (DZNE), Munich, Munich, Germany.

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA) -CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA) -CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA) conjugates and pre-aggregated carrier-free (GA) . Only ovalbumin-(GA) immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA) immunization largely rescued the motor function in (GA) -CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA) -immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.
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http://dx.doi.org/10.15252/emmm.201910919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005532PMC
February 2020

Directional topography gradients drive optimum alignment and differentiation of human myoblasts.

J Tissue Eng Regen Med 2019 12 10;13(12):2234-2245. Epub 2019 Nov 10.

Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Tissue engineering of skeletal muscle aims to replicate the parallel alignment of myotubes on the native tissue. Directional topography gradients allow the study of the influence of topography on cellular orientation, proliferation, and differentiation, resulting in yield cues and clues to develop a proper in vitro environment for muscle tissue engineering. In this study, we used a polydimethylsiloxane-based substrate containing an aligned topography gradient with sinusoidal features ranging from wavelength (λ) = 1,520 nm and amplitude (A) =176 nm to λ = 9,934 nm and A = 2,168 nm. With this topography gradient, we evaluated the effect of topography on human myoblasts distribution, dominant orientation, cell area, nuclei coverage, cell area per number of nuclei, and nuclei area of myotubes. We showed that human myoblasts aligned and differentiated irrespective of the topography section. In addition, aligned human myotubes showed functionality and maturity by contracting spontaneously and nuclei peripheral organization resembling natural myotubes.
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http://dx.doi.org/10.1002/term.2976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973069PMC
December 2019

Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3.

Acta Neuropathol 2020 01 23;139(1):99-118. Epub 2019 Oct 23.

German Center for Neurodegenerative Diseases (DZNE) Munich, 81377, Munich, Germany.

Repeat expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in C9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in C9orf72 patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine-arginine and poly-proline-arginine increased foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM), a major sensor of DSBs, whereas poly-glycine-alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of C9orf72 patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in C9orf72 patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB.
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http://dx.doi.org/10.1007/s00401-019-02082-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942035PMC
January 2020

Transcranial direct current stimulation reduces seizure frequency in patients with refractory focal epilepsy: A randomized, double-blind, sham-controlled, and three-arm parallel multicenter study.

Brain Stimul 2020 Jan - Feb;13(1):109-116. Epub 2019 Sep 24.

Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Neuromodulation, Beijing, China.

Background: Transcranial direct current stimulation (tDCS) has been explored in epilepsy with limited samples, varied parameters, and inconclusive results. We aimed to study the efficacy of tDCS for patients with refractory focal epilepsy.

Method: We conducted a randomized, double-blind, sham-controlled, and three-arm (Group 1 (sham), Group 2 (20-min), and Group 3 (2 × 20-min)) tDCS parallel multicenter study. The primary outcome measurement was seizure frequencies (SFs). The study consisted of 28-days baseline, 14-days treatment, and 56-days follow-up. The cathode was placed over the epileptogenic focus, and the current intensity was 2 mA. The generalized estimating equations model, one-way analysis of variance, chi-square and Kruskal-Wallis test were used for analysis.

Results: Of the 82 enrolled patients, 70 patients were included for final analysis (Group 1, n = 21; Group 2, n = 24; and Group 3, n = 25). There was a significant reduction in SFs for both active tDCS groups compared with the sham group. Patients in Group 2 showed a significantly 50.73-21.91% greater reduction in SFs that lasted for 4 weeks (p = 0.008-0.060). Patients in Group 3 showed a significantly 63.19-49.79% greater reduction in SFs compared with the sham group that lasted for 5 weeks (p = 0.011-0.045). Patients in Group 3 had a 64.98-66.32% greater reduction in SFs at W9-W10, when compared with Group 2 (p = 0.021-0.022).

Conclusion: Fourteen consecutive days tDCS significantly decreased SFs in patients with refractory focal epilepsy, with 2 × 20-min daily stimulation protocol being superior to 20-min daily stimulation protocol.
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http://dx.doi.org/10.1016/j.brs.2019.09.006DOI Listing
June 2020

Graphene-Based THz Absorber with a Broad Band for Tuning the Absorption Rate and a Narrow Band for Tuning the Absorbing Frequency.

Nanomaterials (Basel) 2019 Aug 8;9(8). Epub 2019 Aug 8.

College of Electronic Science and Technology, National University of Defense Technology, Changsha 410073, China.

In this paper, we propose a broadband absorption-controllable absorber based on nested nanostructure graphene and a narrowband frequency-tunable absorber utilizing gold-graphene hybrid structure in the terahertz regime. The numerical simulation results showed that the absorption of the broadband absorber can be changed from 27% to more than 90% over 0.75 to 1.7 THz by regulating the chemical potential of graphene. With the same regulation mechanism, the absorbing peak of the narrowband absorber can be moved from 2.29 to 2.48 THz continuously with absorption of 90%. Furthermore, via the cascade of the two types of absorbers, an independently tunable dual-band absorber is constituted. Its absorption spectrum is the superposition of absorption-controllable absorber and frequency-tunable absorber. The absorptivity and operating frequency of the two absorbing bands can be tuned independently without mutual inference. Moreover, it is insensitive to the polarization and it maintains high absorption over a wide range of incident angle. For the flexibility, tunability as well as the independence of polarization and angle, this design has wide prospects in various applications.
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http://dx.doi.org/10.3390/nano9081138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722701PMC
August 2019

Doxycycline inhibits NAcht Leucine-rich repeat Protein 3 inflammasome activation and interleukin-1β production induced by Porphyromonas gingivalis-lipopolysaccharide and adenosine triphosphate in human gingival fibroblasts.

Arch Oral Biol 2019 Nov 2;107:104514. Epub 2019 Aug 2.

Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China. Electronic address:

Objective: To investigate the effect of adenosine triphosphate (ATP) on inflammasome activation by Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS) stimulation and the anti-inflammatory eff ;ect of doxycycline (Dox) in human gingival fibroblasts (HGFs).

Design: The optimal concentration of P. gingivalis-LPS (1.0 μg/mL) for cellular viability was determined by observing cell morphology and measuring the amount of formazan and the expression of pro-caspase-1. The expression of genes and proteins related to the NAcht Leucine-rich repeat Protein 3 (NLRP3) inflammasome, including NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1 and its activated forms, and the inflammatory factor interleukin-1β (IL-1β) and its activated forms were measured.

Results: The NLRP3 inflammasome (i.e., NLRP3, ASC, caspase-1) was not affected by stimulation with P. gingivalis-LPS or ATP. However, a combination of P. gingivalis-LPS and ATP significantly enhanced inflammasome activation and IL-1β production at the gene and protein levels as measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Furthermore, doxycycline addition markedly inhibited inflammasome activation and IL-1β production induced by a combination of P. gingivalis-LPS and ATP.

Conclusions: LPS, ATP, and doxycycline play critical roles in regulating host immune responses. This evidence provides guidance for the application of tetracycline drugs for the clinical treatment of periodontal disease.
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http://dx.doi.org/10.1016/j.archoralbio.2019.104514DOI Listing
November 2019