Publications by authors named "Biao Ren"

118 Publications

Novel dental implant modifications with two-staged double benefits for preventing infection and promoting osseointegration and .

Bioact Mater 2021 Dec 15;6(12):4568-4579. Epub 2021 May 15.

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

Peri-implantitis are a major problem causing implant failure these days. Accordingly, anti-infection during the early stage and subsequent promotion of osseointegration are two main key factors to solve this issue. Micro-arc oxidation (MAO) treatment is a way to form an oxidation film on the surface of metallic materials. The method shows good osteogenic properties but weak antibacterial effect. Therefore, we developed combined strategies to combat severe peri-implantitis, which included the use of a novel compound, PD, comprising dendrimers poly(amidoamine) (PAMAM) loading dimethylaminododecyl methacrylate (DMADDM) as well as MAO treatment. Here, we explored the chemical properties of the novel compound PD, and proved that this compound was successfully synthesized, with the loading efficiency and encapsulation efficiency of 23.91% and 31.42%, respectively. We further report the two-stage double benefits capability of PD + MAO: (1) in the first stage, PD + MAO could decrease the adherence and development of biofilms by releasing DMADDM in the highly infected first stage after implant surgery both and ; (2) in the second stage, PD + MAO indicated mighty anti-infection and osteoconductive characteristics in a rat model of peri-implantitis . This study first reports the two-staged, double benefits of PD + MAO, and demonstrates its potential in clinical applications for inhibiting peri-implantitis, especially in patients with severe infection risk.
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http://dx.doi.org/10.1016/j.bioactmat.2021.04.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141509PMC
December 2021

Corrigendum: Reactive Oxygen Species in Pathogen Clearance: The Killing Mechanisms, the Adaption Response, and the Side Effects.

Front Microbiol 2021 13;12:685133. Epub 2021 May 13.

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

[This corrects the article DOI: 10.3389/fmicb.2020.622534.].
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http://dx.doi.org/10.3389/fmicb.2021.685133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152934PMC
May 2021

Synonymous point mutation of gtfB gene caused by therapeutic X-rays exposure reduced the biofilm formation and cariogenic abilities of Streptococcus mutans.

Cell Biosci 2021 May 17;11(1):91. Epub 2021 May 17.

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

Background: The shift of oral microbiota is a critical factor of radiation caries in head and neck cancer patients after the radiotherapy. However, the direct effects of irradiation on the genome and virulence of cariogenic bacteria are poorly described. Here we investigated the genomic mutations and virulence change of Streptococcus mutans (S. mutans), the major cariogenic bacteria, exposed to the therapeutic doses of X-rays.

Results: X-ray reduced the survival fraction of S. mutans and impacted its biofilm formation. We isolated a biofilm formation-deficient mutant #858 whose genome only possessed three synonymous mutations (c.2043 T > C, c.2100C > T, c.2109A > G) in gtfB gene. The "silent mutation" of c.2043 T > C in gtfB gene can cause the down-regulation of all of the gtfs genes' expression and decrease the GtfB enzyme secretion without the effect on the growth due to the codon bias. #858 and synonymous point mutation strain gtfB , similar to the gtfB gene null mutant Δ gtfB, can significantly decrease the extracellular polysaccharide production, biofilm formation and cariogenic capabilities both in vitro and in vivo compared with wild type.

Conclusion: The direct exposure of X-ray radiation can affect the genome and virulence of oral bacteria even at therapeutic doses. The synonymous mutations of genome are negligent factors for gene expression and related protein translation due to the codon usage frequency.
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http://dx.doi.org/10.1186/s13578-021-00608-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130306PMC
May 2021

The cross-kingdom interaction between Helicobacter pylori and Candida albicans.

PLoS Pathog 2021 May 6;17(5):e1009515. Epub 2021 May 6.

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

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http://dx.doi.org/10.1371/journal.ppat.1009515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101746PMC
May 2021

The Role of Neutrophil Extracellular Traps in Periodontitis.

Front Cell Infect Microbiol 2021 18;11:639144. Epub 2021 Mar 18.

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

Periodontitis is a chronic, destructive disease of periodontal tissues caused by multifaceted, dynamic interactions. Periodontal bacteria and host immunity jointly contribute to the pathological processes of the disease. The dysbiotic microbial communities elicit an excessive immune response, mainly by polymorphonuclear neutrophils (PMNs). As one of the main mechanisms of PMN immune response in the oral cavity, neutrophil extracellular traps (NETs) play a crucial role in the initiation and progression of late-onset periodontitis. NETs are generated and released by neutrophils stimulated by various irritants, such as pathogens, host-derived mediators, and drugs. Chromatin and proteins are the main components of NETs. Depending on the characteristics of the processes, three main pathways of NET formation have been described. NETs can trap and kill pathogens by increased expression of antibacterial components and identifying and trapping bacteria to restrict their spread. Moreover, NETs can promote and reduce inflammation, inflicting injuries on the tissues during the pro-inflammation process. During their long-term encounter with NETs, periodontal bacteria have developed various mechanisms, including breaking down DNA of NETs, degrading antibacterial proteins, and impacting NET levels in the pocket environment to resist the antibacterial function of NETs. In addition, periodontal pathogens can secrete pro-inflammatory factors to perpetuate the inflammatory environment and a friendly growth environment, which are responsible for the progressive tissue damage. By learning the strategies of pathogens, regulating the periodontal concentration of NETs becomes possible. Some practical ways to treat late-onset periodontitis are reducing the concentration of NETs, administering anti-inflammatory therapy, and prescribing broad-spectrum and specific antibacterial agents. This review mainly focuses on the mechanism of NETs, pathogenesis of periodontitis, and potential therapeutic approaches based on interactions between NETs and periodontal pathogens.
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http://dx.doi.org/10.3389/fcimb.2021.639144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012762PMC
March 2021

Interactions Between Neutrophils and Periodontal Pathogens in Late-Onset Periodontitis.

Front Cell Infect Microbiol 2021 12;11:627328. Epub 2021 Mar 12.

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

Late-onset periodontitis is associated with a series of inflammatory reactions induced by periodontal pathogens, such as , a keystone pathogen involved in periodontitis. Neutrophils are the most abundant leukocytes in the periodontal pocket/gingival crevice and inflamed periodontal tissues. They form a "wall" between the dental plaque and the junctional epithelium, preventing microbial invasion. The balance between neutrophils and the microbial community is essential to periodontal homeostasis. Excessive activation of neutrophils in response to periodontal pathogens can induce tissue damage and lead to periodontitis persistence. Therefore, illuminating the interactions between neutrophils and periodontal pathogens is critical for progress in the field of periodontitis. The present review aimed to summarize the interactions between neutrophils and periodontal pathogens in late-onset periodontitis, including neutrophil recruitment, neutrophil mechanisms to clear the pathogens, and pathogen strategies to evade neutrophil-mediated elimination of bacteria. The recruitment is a multi-step process, including tethering and rolling, adhesion, crawling, and transmigration. Neutrophils clear the pathogens mainly by phagocytosis, respiratory burst responses, degranulation, and neutrophil extracellular trap (NET) formation. The mechanisms that pathogens activate to evade neutrophil-mediated killing include impairing neutrophil recruitment, preventing phagocytosis, uncoupling killing from inflammation, and resistance to ROS, degranulation products, and NETs.
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http://dx.doi.org/10.3389/fcimb.2021.627328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994856PMC
March 2021

Candida albicans CHK1 gene from two-component system is essential for its pathogenicity in oral candidiasis.

Appl Microbiol Biotechnol 2021 Mar 26;105(6):2485-2496. Epub 2021 Feb 26.

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

The roles of Candida albicans CHK1, a key gene from two-component system, in oral mucosal infection are not clear. This study evaluated the key roles of CHK1 gene in vitro and in vivo. The expression of CHK1 and its regulated virulence factors were tested during the oral epithelial cell infection. The production of lactate dehydrogenase, ROS, and IL-1α combined with the confocal and scanning electron microscope observation was employed to identify the capability of CHK1 in damaging the epithelial cells. Both immunocompetent and immunodeficient mice oropharyngeal infection models were involved to confirm the roles of CHK1 gene in vivo. The expression of CHK1 gene was significantly increased during the oral epithelial cell infection. The chk1Δ/Δ mutant failed to damage the epithelial cells or induce IL-α and ROS production. Interestingly, chk1Δ/Δ can also form the similar hyphae with WT and complementary strains. Accordingly, chk1Δ/Δ did not affect the adhesion and invasion rates of C. albicans to oral epithelial cells. However, chk1Δ/Δ significantly decreased the expression levels of the virulence factors, including ALS2, SAP6, and YWP1. The chk1Δ/Δ also failed to cause oral candidiasis in both immunocompetent and immunodeficient mice indicating that CHK1 gene from the two-component system is essential for the pathogenicity of C. albicans. KEY POINTS: • CHK1gene is essential for C. albicans in oral candidiasis • C. albicans without CHK1 gene can form "non-pathogenic" hyphae. • CHK1 gene regulates the virulence of C. albicans.
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http://dx.doi.org/10.1007/s00253-021-11187-0DOI Listing
March 2021

Reactive Oxygen Species in Pathogen Clearance: The Killing Mechanisms, the Adaption Response, and the Side Effects.

Front Microbiol 2020 4;11:622534. Epub 2021 Feb 4.

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

Reactive oxygen species (ROS) are attractive weapons in both antibiotic-mediated killing and host-mediated killing. However, the involvement of ROS in antibiotic-mediated killing and complexities in host environments challenge the paradigm. In the case of bacterial pathogens, the examples of some certain pathogens thriving under ROS conditions prompt us to focus on the adaption mechanism that pathogens evolve to cope with ROS. Based on these, we here summarized the mechanisms of ROS-mediated killing of either antibiotics or the host, the examples of bacterial adaption that successful pathogens evolved to defend or thrive under ROS conditions, and the potential side effects of ROS in pathogen clearance. A brief section for new antibacterial strategies centered around ROS was also addressed.
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http://dx.doi.org/10.3389/fmicb.2020.622534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889972PMC
February 2021

Starvation Survival and Biofilm Formation under Subminimum Inhibitory Concentration of QAMs.

Biomed Res Int 2021 14;2021:8461245. Epub 2021 Jan 14.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics & Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

Quaternary ammonium methacrylates (QAMs) are useful antimicrobial compounds against oral bacteria. Here, we investigated the effects of two QAMs, dimethylaminododecyl methacrylate (DMADDM) and dimethylaminohexadecyl methacrylate (DMAHDM), on biofilm formation, survival and development of tolerance by biofilm, and survival and development of tolerance against QAMs after prolonged starvation. (. ), (. ), (. ), and (. ) were used. Minimum inhibitory concentration (MIC) of QAMs against multispecies biofilm was determined. Biofilm formed under sub-MIC was observed by crystal violet staining and confocal laser scanning microscopy (CLSM). Metabolic activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactic acid production measurement. Development of tolerance was determined by MIC values before and after exposure to QAMs or after prolonged starvation. It was found that . and . could survive and form biofilm under sub-MIC of QAMs. Lactic acid production from biofilms formed under sub-MIC was significantly higher than control specimens ( < 0.05). The exposure to sub-MIC of QAMs promoted biofilm formation, and prolonged starvation or prolonged contact with sub-MIC helped bacteria develop tolerance against killing by QAMs.
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http://dx.doi.org/10.1155/2021/8461245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822668PMC
June 2021

[Effects of Artemisinin and Its Derivatives on Oral Microbes].

Sichuan Da Xue Xue Bao Yi Xue Ban 2020 Nov;51(6):760-766

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

The oral environment provides suitable conditions for the colonization of various microorganisms. However, the oral microbials could be the initial factors of some kinds of oral infectious diseases, therefore the treatment against oral microbial pathogens has become an effective strategy. Artemisinin, a kind of sesquiterpene lactone extracted from Traditional Chinese Medicine , is the first-line therapy to treat tertian malaria, subtertian malaria and anti-chloroquine malaria for its high efficiency and low toxicity. In recent years, artemisinin and its derivatives have also been proven to be effective against bacteria, fungi, viruses, parasites, and tumors, some of which are closely related to oral diseases. In this review, we summarize the potential effects of artemisinin and its derivatives on oral microorganism by analyzing previous research and latest progress to provide the evidence for further improvement, and look forward to the new research directions. Further studies are needed to improve existing technologies and standards to clarify the effects of artemisinin and its derivatives on microorganisms with controversial effects, to expand the detection of microorganisms associated with oral infectious diseases, and to clarify the interaction with existing antifungal agents in the field of antifungal diseases. In addition, in the study of anti-oral infectious diseases, artemisinin and its derivatives' administration scheme, potential drug interactions, toxic and side effects and other aspects are necessary conditions for further research, which is also a new direction of research. With the maturity of the production process, the improvement of relevant research and the potential demand for the treatment of oral infectious diseases, artemisinin and its derivatives have a broad prospect in the field of oral microorganisms, and provide a new opportunity for the research and development of oral drugs.
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http://dx.doi.org/10.12182/20201160502DOI Listing
November 2020

[Synergistic Antibacterial Activity of Berberine in Combination with Amylmetacresol Against ].

Sichuan Da Xue Xue Bao Yi Xue Ban 2020 Nov;51(6):749-754

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

Objective: To study the antibacterial effect of berberine combined with amylmetacresol on .

Methods: Both dilution method and live bacteria CFU were used to determine the minimum inhibitory concentration (MIC) of berberine and amylmetacresol on . The killing effect of berberine and amylmetacresol on planktonic was detected by suspension quantitative germicidal test and live/dead bacteria staining. The effects of berberine and amylmetacresol on the structure of mature biofilm of was observed by scanning electron microscopy (SEM). The toxicity of berberine and amylmetacresol on human oral keratinocytes (HOK) was determined by CCK-8 cell proliferation and cytotoxicity assay and cytotoxicity LDH assay.

Results: The MIC of berberine was 512 μg/mL, and the MIC of amylmetacresol was 0.023 3%. 512 μg/mL berberine and 0.002 33% amylmetacresol had a weak killing effect on planktonic alone, while they showed a synergistic antibacterial effect in combination. Cell survival in the biofilm was only slightly changed by berberine and amylmetacresol. The structure of biofilm was obviously changed by berberine and amylmetacresol. 512 μg/mL berberine and 0.002 33% amylmetacresol alone or in combination showed the survival rate was much higher than the injury rate, suggesting berberine and amylmetacresol had a low cytotoxicity.

Conclusion: Berberine and amylmetacresol had synergism against , and the biological safety of the combination use was better.
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http://dx.doi.org/10.12182/20201160501DOI Listing
November 2020

[Ergosterol Pathway of Promotes the Growth and Cariogenic Virulence of ].

Sichuan Da Xue Xue Bao Yi Xue Ban 2020 Nov;51(6):742-748

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

Objective: To investigate the effect of ( ) on proliferation and virulence of ( ), and to verify the role of the ergosterol pathway in it.

Methods: After single- and co-cultivation of wild-type 5314 and UA159, the absorbance value of OD and colony-forming units (CFU) were detected to reflect the influence of on the growth of . To reflect the influence of on the virulence of , the production of extracellular polysaccharides was detected by anthrone-vitriol method, and the acid production capacity was detected by a pH meter. After single- and co-cultivation of mutant strains and , the growth of was evaluated by CFU. After inhibiting the ergosterol pathway by 0 mg/L, 0.012 5 mg/L, and 0.025 mg/L fluconazole for 24 h, the CFU of single- and co-cultivated wild-type and were detected.

Results: The OD absorbance value and CFU in theco-cultivation of . wild-type and was higher than that in the single culture ( <0.05), and the production of extracellular polysaccharides in was increased when was co-cultured with ( <0.05), accompanied with a more obvious decrease of pH ( <0.05). Fourteen strains in whole 42 mutant strains lost the growth-promoting effect on , including 6 ergosterol synthesis-related mutant strains. After co-cultivation of the 6 ergosterol synthesis-related mutant strains and , the CFU of remained unchanged or decreased. After inhibiting the ergosterol pathway by 0.012 5 mg/L and 0.025 mg/L fluconazole, the CFU of in the co-cultivation of wild-type and was lower than that without fluconazole treatment ( <0.05), while the CFU of and single-cultivations did not change significantly ( >0.05) and the CFU of in the co-cultivation of wild-type and did not change significantly ( >0.05).

Conclusion: can enhance the growth ability and virulence of through the ergosterol-related pathway. This process can be inhibited by fluconazole, which is expected to become a novel strategy to prevent and treat dental caries.
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http://dx.doi.org/10.12182/20201160203DOI Listing
November 2020

Generation of Fluorinated Amychelin Siderophores against Pseudomonas aeruginosa Infections by a Combination of Genome Mining and Mutasynthesis.

Cell Chem Biol 2020 12 12;27(12):1532-1543.e6. Epub 2020 Nov 12.

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address:

Pioneering microbial genomic surveys have revealed numerous untapped biosynthetic gene clusters, unveiling the great potential of new natural products. Here, using a combination of genome mining, mutasynthesis, and activity screening in an infection model comprising Caenorhabditis elegans and Pseudomonas aeruginosa, we identified candidate virulence-blocking amychelin siderophore compounds from actinomycetes. Subsequently, we developed unreported analogs of these virulence-blocking siderophores with improved potency by exploiting an Amycolatopsis methanolica strain 239 chorismate to salicylate a biosynthetic subpathway for mutasynthesis. This allowed us to generate the fluorinated amychelin, fluoroamychelin I, which rescued C. elegans from P. aeruginosa-mediated killing with an EC value of 1.4 μM, outperforming traditional antibiotics including ceftazidime and meropenem. In general, this paper describes an efficient platform for the identification and production of classes of anti-microbial compounds with potential unique modes of action.
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http://dx.doi.org/10.1016/j.chembiol.2020.10.009DOI Listing
December 2020

Candida albicans promotes tooth decay by inducing oral microbial dysbiosis.

ISME J 2021 03 4;15(3):894-908. Epub 2020 Nov 4.

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

Candida albicans has been detected in root carious lesions. The current study aimed to explore the action of this fungal species on the microbial ecology and the pathogenesis of root caries. Here, by analyzing C. albicans in supragingival dental plaque collected from root carious lesions and sound root surfaces of root-caries subjects as well as caries-free individuals, we observed significantly increased colonization of C. albicans in root carious lesions. Further in vitro and animal studies showed that C. albicans colonization increased the cariogenicity of oral biofilm by altering its microbial ecology, leading to a polymicrobial biofilm with enhanced acidogenicity, and consequently exacerbated tooth demineralization and carious lesion severity. More importantly, we demonstrated that the cariogenicity-promoting activity of C. albicans was dependent on PHR2. Deletion of PHR2 restored microbial equilibrium and led to a less cariogenic biofilm as demonstrated by in vitro artificial caries model or in vivo root-caries rat model. Our data indicate the critical role of C. albicans infection in the occurrence of root caries. PHR2 is the major factor that determines the ecological impact and caries-promoting activity of C. albicans in a mixed microbial consortium.
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http://dx.doi.org/10.1038/s41396-020-00823-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026629PMC
March 2021

Advances of Anti-Caries Nanomaterials.

Molecules 2020 Oct 30;25(21). Epub 2020 Oct 30.

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

Caries is the most common and extensive oral chronic disease. Due to the lack of anti-caries properties, traditional caries filling materials can easily cause secondary caries and lead to treatment failure. Nanomaterials can interfere with the bacteria metabolism, inhibit the formation of biofilm, reduce demineralization, and promote remineralization, which is expected to be an effective strategy for caries management. The nanotechnology in anti-caries materials, especially nano-adhesive and nano-composite resin, has developed fast in recent years. In this review, the antibacterial nanomaterials, remineralization nanomaterials, and nano-drug delivery systems are reviewed. We are aimed to provide a theoretical basis for the future development of anti-caries nanomaterials.
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http://dx.doi.org/10.3390/molecules25215047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662703PMC
October 2020

[Research progress of Candida albicans on malignant transformation of oral mucosal diseases].

Hua Xi Kou Qiang Yi Xue Za Zhi 2020 Aug;38(4):431-437

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

Oral cancer is the most common malignant tumor in the head and neck, and is one of the world's top ten malignancies. Microbial infection is an important risk factor of oral cancer. Candida albicans is the most popular opportunistic fungal pathogen. Epidemiological studies have shown that Candida albicans is closely tied to oral malignancy. Animal experimentation have also proven that infection of Candida albicans can promote the development of oral epithelial carcinogenesis. The current studies have revealed several mechanisms involved in this process, including destroying the epithelial barrier, producing carcinogenic substances (nitrosamines, acetaldehyde), inducing chronic inflammation, activating immune response, etc. However, current researches on mechanisms are still inadequate, and some hypotheses remain controversial. Here, we review the findings related to Candida albicans' effect on the malignant transformation of oral mucosa, hoping to provide reference for deep research and controlling oral cancer clinically.
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http://dx.doi.org/10.7518/hxkq.2020.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426678PMC
August 2020

Characterization of anti-BCG benz[α]anthraquinones and new siderophores from a Xinjiang desert-isolated rare actinomycete Nocardia sp. XJ31.

Appl Microbiol Biotechnol 2020 Oct 24;104(19):8267-8278. Epub 2020 Aug 24.

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.

The current global demand for novel anti-TB drugs has drawn urgent attention on the discovery of natural product compounds with anti-TB activity. Lots of efforts have emphasized on environmental samples from unexplored or underexplored natural habits and identified numerous rare actinomycete taxa producing structurally diverse bioactive natural products. Herein, we report a survey of the rare actinobacteria diversity in Xinjiang region together with the discovery of anti-TB active natural products from these strains. We have collected 17 soil samples at different sites with different environmental conditions, from which 39 rare actinobacteria were identified by using a selective isolation strategy with 5 media variations. Among those isolated strains, XJ31 was identified as a new Nocardia sp. based on 16S rRNA gene analysis. Through one strain-many compounds (OSMAC) strategy combined with anti-Bacillus Calmette-Guérin bioassay-guided isolation, two groups of compounds were identified. They were twelve siderophores (nocardimicins, 1-12) and two anthraquinones (brasiliquinones, 13 and 14) and ten of them were identified as new compounds. The structures of the purified compounds were elucidated using HR-ESI-MS, 1D NMR, and 2D NMR techniques. The anti-TB bioassays revealed that the two benz[α]anthraquinones have potent activity against BCG (MICs = 25 μM), which can be used as a promising start point for further anti-TB drug development. KEY POINTS: • Ten new natural products were identified from Nocardia sp. XJ31. • Brasiliquinones 13 and 14 showed moderate anti-BCG activity.
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http://dx.doi.org/10.1007/s00253-020-10842-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443361PMC
October 2020

The microbial coinfection in COVID-19.

Appl Microbiol Biotechnol 2020 Sep 11;104(18):7777-7785. Epub 2020 Aug 11.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, NO. 14, 3rd Section of Ren Min Nan Rd. Chengdu, Sichuan, 610041, China.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel β-coronavirus, is the main pathogenic agent of the rapidly spreading pneumonia called coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects much more people, especially the elder population, around the world than other coronavirus, such as SARS-CoV and MERS-CoV, which is challenging current global public health system. Beyond the pathogenesis of SARS-CoV-2, microbial coinfection plays an important role in the occurrence and development of SARS-CoV-2 infection by raising the difficulties of diagnosis, treatment, prognosis of COVID-19, and even increasing the disease symptom and mortality. We summarize the coinfection of virus, bacteria and fungi with SARS-CoV-2, their effects on COVID-19, the reasons of coinfection, and the diagnosis to emphasize the importance of microbial coinfection in COVID-19. KEY POINTS: • Microbial coinfection is a nonnegligible factor in COVID-19. • Microbial coinfection exacerbates the processes of the occurrence, development and prognosis of COVID-19, and the difficulties of clinical diagnosis and treatment. • Different virus, bacteria, and fungi contributed to the coinfection with SARS-CoV-2.
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http://dx.doi.org/10.1007/s00253-020-10814-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417782PMC
September 2020

Molecular networking assisted discovery and biosynthesis elucidation of the antimicrobial spiroketals epicospirocins.

Chem Commun (Camb) 2020 Sep 4;56(70):10171-10174. Epub 2020 Aug 4.

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.

Two pairs of dibenzospiroketal racemates, (±)-epicospirocin A (1a/1b) and (±)-1-epi-epicospirocin A (2a/2b), and two (+)-enantiomers of aspermicrones, ent-aspermicrone B (3b) and ent-aspermicrone C (4b), together with two hemiacetal epimeric mixtures, epicospirocin B/1-epi-epicospirocin B (5/6) and epicospirocin C/1-epi-epicospirocin C (7/8), were investigated from the phytopathogenic fungus Epicoccum nigrum 09116 via MS/MS molecular networking guided isolation and chiral separation for the first time. A plausible epicospirocin biosynthetic pathway was elucidated through in silico gene function annotation together with knock-out experiments. This is the first report that has applied MS/MS molecular networking to identify intermediates correlated with a biosynthetic pathway.
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http://dx.doi.org/10.1039/d0cc03990jDOI Listing
September 2020

[Research progress on the regulation of phenolic compounds of traditional Chinese herbs on oral microbes].

Hua Xi Kou Qiang Yi Xue Za Zhi 2020 Jun;38(3):319-323

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

Phenolic compounds are widely found in natural Chinese medicinal plants and have excellent pharmacological properties, such as antioxidation and anti-inflammation. They are the main pharmacological components of many medicinal Chinese herbs. Oral microbiota, especially its composition and metabolism, is highly related to the balance of oral microecology and plays a key role in the occurrence and development of oral diseases. Recent studies have shown that phenolic compounds of traditional Chinese herbs can prevent and treat oral diseases, such as caries, periodontal disease, and oral mucosal infection, by regulating the composition, metabolites, and virulence of oral microorganisms. This review will summarize and discuss the regulation of phenolic compounds on oral microbes.
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http://dx.doi.org/10.7518/hxkq.2020.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296369PMC
June 2020

Promotes Immunoevasion of Oral Cancer by Protecting Cancer from Macrophage Attack.

J Immunol 2020 07 29;205(1):282-289. Epub 2020 May 29.

State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China;

The relationship of and oral squamous cell carcinoma (OSCC) has been studied for several years. Previous studies have focused on the direct effect of on the activities of primary epithelial cells and OSCC cells. However, the immune system is responsible for mediating cancer development, whether can affect oral cancer immunity has seldom been explored to date. In this study, we investigated the role of in the immunoevasion of OSCC. We evaluated the effect of on the phagocytosis of Cal-27 cells (OSCC cell line) by bone marrow-derived macrophages in vitro and studied the effect of on the growth of OSCC and the polarization of tumor-associated macrophages in vivo. We found that was able to inhibit the phagocytosis of Cal-27 cells by macrophages, and membrane-component molecules of , such as proteins, were speculated to be the effector components. In addition, sustained infection with antibiotics-inactivated promoted OSCC growth in mice and induced the polarization of macrophages into M2 tumor-associated macrophages, which mainly display protumor properties. Transcriptome analysis and quantitative RT-PCR revealed that infection upregulated the expression of genes encoding protumor molecules in Cal-27 cells (, , and ) and in macrophages (, , and ). Our in vitro and in vivo data suggest that can promote immunoevasion of oral cancer by protecting cancer from macrophage attack. To our knowledge, the present study reveals a novel mechanism by which promotes OSCC development.
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http://dx.doi.org/10.4049/jimmunol.1901138DOI Listing
July 2020

The effect of disaggregated nano-hydroxyapatite on oral biofilm in vitro.

Dent Mater 2020 07 13;36(7):e207-e216. Epub 2020 May 13.

State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Centre for Oral Diseases, Sichuan University, Chengdu 610064, China; Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China. Electronic address:

Objective: Agglomeration is a common problem facing the preparation and application of nanomaterials, and whether nano-hydroxyapatite (nano HA) can modulate oral microecology left to be unclear. In this study, nano HA was disaggregated by sodium hexametaphosphate (SHMP) and ultrasonic cavitation to observe whether agglomeration would affect its effect on oral bacterial biofilm.

Methods: Dynamic light scattering (DLS) and scanning electronic microscope (SEM) were used to observe the treatment solutions. Single-species biofilms and multi-species biofilms were treated with 10% nano HA, 10% disaggregated nano HA, 10% micro hydroxyapatite (micro HA) and deionized water (DDW) for 30min and analyzed via MTT assay, lactic acid measurement, SEM and confocal laser scanning microscope (CLSM). Real-time polymerase chain reaction was performed to analyze the biofilm composition.

Results: Ultrasonic cavitation combined with SHMP could significantly reduce the degree of agglomeration of nano HA. Disaggregated nano HA could inhibit bacterial growth and reduce the ability of bacterial biofilm to produce lactic acid and extracellular polysaccharides. There was no significant difference on composition of multi-species biofilms between nano HA and disaggregated nano HA.

Significance: The disaggregated nano-hydroxyapatite could inhibit the metabolism and acid production of oral bacterial biofilm, but did not significantly affect the composition of multi-species biofilms.
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http://dx.doi.org/10.1016/j.dental.2020.04.005DOI Listing
July 2020

Anti-caries effect of resin infiltrant modified by quaternary ammonium monomers.

J Dent 2020 06 4;97:103355. Epub 2020 May 4.

State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, National Clinical Research Centre for Oral Diseases, Sichuan University, Chengdu, 610041, China. Electronic address:

Objectives: Resin infiltrant is used in early enamel caries. However, commercial resin infiltrant lacks persistent antibacterial activity. Dimethylaminododecyl methacrylate (DMADDM) was added to resin infiltrant to give it sustainable antibacterial properties and inhibit demineralization.

Methods: After the application of resin infiltrant to bovine enamel, cytotoxicity, surface roughness, and aesthetics were assessed. A multi-species biofilm was incubated on the enamel disk before and one month after microbial-aging. After a 48-h anaerobic incubation, biomass accumulation, metabolic activity, and lactic acid were analyzed using a crystal violet assay, an MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and a lactic acid assay. Biofilm structure and composition were determined by live/dead staining, exopolysaccharide (EPS) staining, scanning electron microscopy (SEM), and quantitative polymerase chain reaction (qPCR). The depth and content of demineralization were tested by transverse microradiography (TMR).

Results: Incorporating DMADDM did not increase the cytotoxicity or change the physical properties when the mass fraction of the DMADDM was 2.5-10 %. The modification decreased the amount of bacterial biofilm, metabolic activity, lactic acid production, EPS, and the proportion of Streptococcus mutans in the biofilms. It also provided anti-demineralization effects. The surface roughness and antibacterial ability were not changed after one month of microbial-aging.

Conclusion: The incorporation of DMADDM improved the antibacterial and anti-demineralization effects of the material. It demonstrated a sustained antibacterial effect.

Clinical Significance: The antibacterial modification might be a potential choice for future clinical applications to inhibit early enamel caries.
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http://dx.doi.org/10.1016/j.jdent.2020.103355DOI Listing
June 2020

Antibiotic-induced dysbiosis of the rat oral and gut microbiota and resistance to Salmonella.

Arch Oral Biol 2020 Jun 1;114:104730. Epub 2020 May 1.

State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, 610041, China; Dept. of Cariology and Endodontics, West China School of Stomatology, Sichuan University, Chengdu, 610041, China; National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, 610041, China. Electronic address:

Objectives: Antibiotics play a great role in the treatment of infectious diseases, but meantime, they cause great disturbances to host microbiota. Studies on different antibiotic-induced changes in host microbiota are relatively scarce. This study aimed to investigate the changes in oral and gut microbiota and possible alterations of gut resistance to Salmonella induced by the administration of antibiotics.

Methods: The experiment was conducted by administering antibiotics to rats and detecting oral and gut microbiota by 16S rRNA gene sequencing. In second part, after treating with antibiotics or Lactobacillus rhamnosus the rats were infected by Salmonella Typhimurium and the pathogen burden in the gut was counted by colony forming unit assay.

Results: The gut microbiota underwent dramatic changes after both vancomycin and ampicillin treatment. The alpha diversity sharply decreased, and the microbiota composition showed a significant difference. However, the gut microbiota recovered within four weeks after stopping antibiotics administration, although this recovery was incomplete. Oral microbiota did not show significant alterations in both alpha and beta diversities. The number of pathogens in the gut in the control group was significantly lower than that in the antibiotic-treated group but only lasted for the first 4 days after infection.

Conclusions: Antibiotics cause dramatic alterations in the number and diversity of gut microbiota but not oral microbiota. These changes in the gut microbiota could incompletely recover four weeks later. When infected with pathogens after antibiotic administration, the rats show a decrease in colonization resistance in the gut for the first four days after infection.
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http://dx.doi.org/10.1016/j.archoralbio.2020.104730DOI Listing
June 2020

Saliva is a non-negligible factor in the spread of COVID-19.

Mol Oral Microbiol 2020 08 31;35(4):141-145. Epub 2020 May 31.

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

SARS-CoV-2, a novel emerging coronavirus, has caused severe disease (COVID-19), and rapidly spread worldwide since the beginning of 2020. SARS-CoV-2 mainly spreads by coughing, sneezing, droplet inhalation, and contact. SARS-CoV-2 has been detected in saliva samples, making saliva a potential transmission route for COVID-19. The participants in dental practice confront a particular risk of SARS-CoV-2 infection due to close contact with the patients and potential exposure to saliva-contaminated droplets and aerosols generated during dental procedures. In addition, saliva-contaminated surfaces could lead to potential cross-infection. Hence, the control of saliva-related transmission in the dental clinic is critical, particularly in the epidemic period of COVID-19. Based on our experience of the COVID-19 epidemic, some protective measures that can help reduce the risk of saliva-related transmission are suggested, in order to avoid the potential spread of SARS-CoV-2 among patients, visitors, and dental practitioners.
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http://dx.doi.org/10.1111/omi.12289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267240PMC
August 2020

The regulation of hyphae growth in .

Virulence 2020 12;11(1):337-348

State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China.

In the last decades, has served as the leading causal agent of life-threatening invasive infections with mortality rates approaching 40% despite treatment. exists in three biological phases: yeast, pseudohyphae, and hyphae. Hyphae, which represent an important phase in the disease process, can cause tissue damage by invading mucosal epithelial cells then leading to blood infection. In this review, we summarized recent results from different fields of fungal cell biology that are instrumental in understanding hyphal growth. This includes research on the differences among phases; the regulatory mechanism of hyphal growth, extension, and maintaining cutting-edge polarity; cross regulations of hyphal development and the virulence factors that cause serious infection. With a better understanding of the mechanism on mycelium formation, this review provides a theoretical basis for the identification of targets in candidiasis treatment. It also gives some reference to the study of antifungal drugs.
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http://dx.doi.org/10.1080/21505594.2020.1748930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161696PMC
December 2020

Publisher Correction: Research on oral microbiota of monozygotic twins with discordant caries experience - in vitro and in vivo study.

Sci Rep 2020 Mar 10;10(1):4728. Epub 2020 Mar 10.

State Key Laboratory of Oral Diseases, Sichuan University, 610041, Chengdu, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-61785-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062769PMC
March 2020

Transmission routes of 2019-nCoV and controls in dental practice.

Int J Oral Sci 2020 03 3;12(1). Epub 2020 Mar 3.

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

A novel β-coronavirus (2019-nCoV) caused severe and even fetal pneumonia explored in a seafood market of Wuhan city, Hubei province, China, and rapidly spread to other provinces of China and other countries. The 2019-nCoV was different from SARS-CoV, but shared the same host receptor the human angiotensin-converting enzyme 2 (ACE2). The natural host of 2019-nCoV may be the bat Rhinolophus affinis as 2019-nCoV showed 96.2% of whole-genome identity to BatCoV RaTG13. The person-to-person transmission routes of 2019-nCoV included direct transmission, such as cough, sneeze, droplet inhalation transmission, and contact transmission, such as the contact with oral, nasal, and eye mucous membranes. 2019-nCoV can also be transmitted through the saliva, and the fetal-oral routes may also be a potential person-to-person transmission route. The participants in dental practice expose to tremendous risk of 2019-nCoV infection due to the face-to-face communication and the exposure to saliva, blood, and other body fluids, and the handling of sharp instruments. Dental professionals play great roles in preventing the transmission of 2019-nCoV. Here we recommend the infection control measures during dental practice to block the person-to-person transmission routes in dental clinics and hospitals.
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http://dx.doi.org/10.1038/s41368-020-0075-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054527PMC
March 2020

Dimethylaminododecyl methacrylate inhibits Candida albicans and oropharyngeal candidiasis in a pH-dependent manner.

Appl Microbiol Biotechnol 2020 Apr 3;104(8):3585-3595. Epub 2020 Mar 3.

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

The prevalence of stomatitis, especially that caused by Candida albicans, has highlighted the need for new antifungal agents. We previously found that a type of quaternary ammonium salts, dimethylaminododecyl methacrylate (DMADDM), incorporated in dental materials inhibited the growth and hyphal development of C. albicans. However, how the quaternary ammonium salts inhibited the fungal pathogens and whether the oral condition, such as salivary pH variation under different diseases, can affect the antimicrobial capacity of quaternary ammonium salts is unknown. This study evaluated the antifungal effects of DMADDM at different pH in vitro and in vivo. A pH-dependent antifungal effect of DMADDM was observed in planktonic and biofilm growth. DMADDM enhanced antifungal activity at alkaline pH. Two pH-regulated genes (PHR1/PHR2) of C. albicans were correlated with the pH-dependent antifungal effects of DMADDM. The PHR1/PHR2 genes and pH values regulated the zeta potential of C. albicans, which then influenced the binding between C. albicans cells and DMADDM. The pH-dependent antifungal activity of DMADDM was then substantiated in a murine oropharyngeal candidiasis model. We directly demonstrated that the antifungal abilities of quaternary ammonium salts relied on the cell zeta potential which affected the binding between fungal cells and quaternary ammonium salts. These findings suggest a new antifungal mechanism of quaternary ammonium under different pH and that DMADDM can be a potential antifungal agent applied in dental materials and stomatitis therapy.Key Points • DMADDM has stronger antifungal activity in alkaline than in acidic pH conditions. • The pH values and pH-regulated genes can affect the zeta potential of fungal cells. • Zeta potential of fungal cells directly affect the binding between DMADDM and cells. Graphical abstract Schematic diagram of the antifungal activities of DMADDM at different pH values.
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http://dx.doi.org/10.1007/s00253-020-10496-0DOI Listing
April 2020

Application of Antibiotics/Antimicrobial Agents on Dental Caries.

Biomed Res Int 2020 31;2020:5658212. Epub 2020 Jan 31.

State Key Laboratory of Oral Disease, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu 610064, China.

Dental caries is the most common oral disease. The bacteriological aetiology of dental caries promotes the use of antibiotics or antimicrobial agents to prevent this type of oral infectious disease. Antibiotics have been developed for more than 80 years since Fleming discovered penicillin in 1928, and systemic antibiotics have been used to treat dental caries for a long time. However, new types of antimicrobial agents have been developed to fight against dental caries. The purpose of this review is to focus on the application of systemic antibiotics and other antimicrobial agents with respect to their clinical use to date, including the history of their development, and their side effects, uses, structure types, and molecular mechanisms to promote a better understanding of the importance of microbial interactions in dental plaque and combinational treatments.
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http://dx.doi.org/10.1155/2020/5658212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013294PMC
November 2020