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author:("Li, jiao")
1.  Molecule Targeting Glucosyltransferase Inhibits Streptococcus mutans Biofilm Formation and Virulence 
Dental plaque biofilms are responsible for numerous chronic oral infections and cause a severe health burden. Many of these infections cannot be eliminated, as the bacteria in the biofilms are resistant to the host's immune defenses and antibiotics. There is a critical need to develop new strategies to control biofilm-based infections. Biofilm formation in Streptococcus mutans is promoted by major virulence factors known as glucosyltransferases (Gtfs), which synthesize adhesive extracellular polysaccharides (EPS). The current study was designed to identify novel molecules that target Gtfs, thereby inhibiting S. mutans biofilm formation and having the potential to prevent dental caries. Structure-based virtual screening of approximately 150,000 commercially available compounds against the crystal structure of the glucosyltransferase domain of the GtfC protein from S. mutans resulted in the identification of a quinoxaline derivative, 2-(4-methoxyphenyl)-N-(3-{[2-(4-methoxyphenyl)ethyl]imino}-1,4-dihydro-2-quinoxalinylidene)ethanamine, as a potential Gtf inhibitor. In vitro assays showed that the compound was capable of inhibiting EPS synthesis and biofilm formation in S. mutans by selectively antagonizing Gtfs instead of by killing the bacteria directly. Moreover, the in vivo anti-caries efficacy of the compound was evaluated in a rat model. We found that the compound significantly reduced the incidence and severity of smooth and sulcal-surface caries in vivo with a concomitant reduction in the percentage of S. mutans in the animals' dental plaque (P < 0.05). Taken together, these results represent the first description of a compound that targets Gtfs and that has the capacity to inhibit biofilm formation and the cariogenicity of S. mutans.
PMCID: PMC4704189  PMID: 26482298
2.  Irisin: A myokine with locomotor activity 
Neuroscience letters  2015;595:7-11.
The mechanisms underlying alterations in brain functions in response to physical exercise are not fully understood. The present study examined the central effect of irisin, a 112 amino acid polypeptide hormone secreted from the skeletal muscle after exercise, on the locomotion in rats. Central administration of irisin significantly increased the locomotion. Relative to control animals treated with IgG Fc peptide, rats receiving irisin demonstrated a marked increase in total travel distance, ambulatory counts and time, and vertical counts and time. These changes were associated with a significant decrease in resting time. Central treatment of irisin also induced significant increases in oxygen consumption, carbon dioxide production and heat production, indicating an increase in metabolic activity. Our study suggests that physical activity may signal to the central nervous system to coordinate locomotion with metabolic activity via irisin.
PMCID: PMC4836606  PMID: 25841790
Irisin; Locomotion; Metabolism; Central nervous system
3.  Preliminary analysis of salivary microbiome and their potential roles in oral lichen planus 
Scientific Reports  2016;6:22943.
Several studies have explored the origin and development mechanism of oral lichen planus (OLP) with limited attention to the role of bacteria in the progression of this common oral disease. Here we utilized MiSeq sequencing of 16S rRNA gene amplicons to identify complex oral microbiota associated with OLP from saliva samples of two subtypes (reticular and erosive) of OLP patients and healthy controls. Our analyses indicated that the overall structure of the salivary microbiome was not significantly affected by disease status. However, we did observe evident variations in abundance for several taxonomic groups in OLP. Porphyromonas and Solobacterium showed significantly higher relative abundances, whereas Haemophilus, Corynebacterium, Cellulosimicrobium and Campylobacter showed lower abundances in OLP patients, as compared with healthy controls. In addition, we explored specific microbial co-occurrence patterns in OLP, and revealed significantly fewer linkers of Streptococcus comprising species in erosive OLP. Furthermore, the disease severity and immune dysregulation were also genus-associated, including with Porphyromonas that correlated to disease scores and salivary levels of interleukin (IL)-17 and IL-23. Overall, this study provides a general description of oral microbiome in OLP, and it will be useful for further investigation of their potential roles in the initiation and immune modulation of OLP.
PMCID: PMC4785528  PMID: 26961389
4.  Inhibition of Streptococcus mutans polysaccharide synthesis by molecules targeting glycosyltransferase activity 
Journal of Oral Microbiology  2016;8:10.3402/jom.v8.31095.
Glycosyltransferase (Gtf) is one of the crucial virulence factors of Streptococcus mutans, a major etiological pathogen of dental caries. All the available evidence indicates that extracellular polysaccharide, particularly glucans produced by S. mutans Gtfs, contribute to the cariogenicity of dental biofilms. Therefore, inhibition of Gtf activity and the consequential polysaccharide synthesis may impair the virulence of cariogenic biofilms, which could be an alternative strategy to prevent the biofilm-related disease. Up to now, many Gtf inhibitors have been recognized in natural products, which remain the major and largely unexplored source of Gtf inhibitors. These include catechin-based polyphenols, flavonoids, proanthocyanidin oligomers, polymeric polyphenols, and some other plant-derived compounds. Metal ions, oxidizing agents, and some other synthetic compounds represent another source of Gtf inhibitors, with some novel molecules either discovered by structure-based virtual screening or synthesized based on key structures of known inhibitors as templates. Antibodies that inhibit one or more Gtfs have also been developed as topical agents. Although many agents have been shown to possess potent inhibitory activity against glucan synthesis by Gtfs, bacterial cell adherence, and caries development in animal models, much research remains to be performed to find out their mechanism of action, biological safety, cariostatic efficacies, and overall influence on the entire oral community. As a strategy to inhibit the virulence of cariogenic microbes rather than eradicate them from the microbial community, Gtf inhibition represents an approach of great potential to prevent dental caries.
PMCID: PMC4841093  PMID: 27105419
inhibitor; glycosyltransferase; S. mutans; dental caries
5.  Phylogenetic and functional gene structure shifts of the oral microbiomes in periodontitis patients 
The ISME Journal  2014;8(9):1879-1891.
Determining the composition and function of subgingival dental plaque is crucial to understanding human periodontal health and disease, but it is challenging because of the complexity of the interactions between human microbiomes and human body. Here, we examined the phylogenetic and functional gene differences between periodontal and healthy individuals using MiSeq sequencing of 16S rRNA gene amplicons and a specific functional gene array (a combination of GeoChip 4.0 for biogeochemical processes and HuMiChip 1.0 for human microbiomes). Our analyses indicated that the phylogenetic and functional gene structure of the oral microbiomes were distinctly different between periodontal and healthy groups. Also, 16S rRNA gene sequencing analysis indicated that 39 genera were significantly different between healthy and periodontitis groups, and Fusobacterium, Porphyromonas, Treponema, Filifactor, Eubacterium, Tannerella, Hallella, Parvimonas, Peptostreptococcus and Catonella showed higher relative abundances in the periodontitis group. In addition, functional gene array data showed that a lower gene number but higher signal intensity of major genes existed in periodontitis, and a variety of genes involved in virulence factors, amino acid metabolism and glycosaminoglycan and pyrimidine degradation were enriched in periodontitis, suggesting their potential importance in periodontal pathogenesis. However, the genes involved in amino acid synthesis and pyrimidine synthesis exhibited a significantly lower relative abundance compared with healthy group. Overall, this study provides new insights into our understanding of phylogenetic and functional gene structure of subgingival microbial communities of periodontal patients and their importance in pathogenesis of periodontitis.
PMCID: PMC4139721  PMID: 24671083
functional gene array; Illumina sequencing; periodontitis; subgingival dental plaque
6.  Streptococcus mutans copes with heat stress by multiple transcriptional regulons modulating virulence and energy metabolism 
Scientific Reports  2015;5:12929.
Dental caries is closely associated with the virulence of Streptococcus mutans. The virulence expression of S. mutans is linked to its stress adaptation to the changes in the oral environment. In this work we used whole-genome microarrays to profile the dynamic transcriptomic responses of S. mutans during physiological heat stress. In addition, we evaluated the phenotypic changes, including, eDNA release, initial biofilm formation, extracellular polysaccharides generation, acid production/acid tolerance, and ATP turnover of S. mutans during heat stress. There were distinct patterns observed in the way that S. mutans responded to heat stress that included 66 transcription factors for the expression of functional genes being differentially expressed. Especially, response regulators of two component systems (TCSs), the repressors of heat shock proteins and regulators involved in sugar transporting and metabolism co-ordinated to enhance the cell’s survival and energy generation against heat stress in S. mutans.
PMCID: PMC4528225  PMID: 26251057
7.  Central and Peripheral Irisin Differentially Regulate Blood Pressure 
Irisin is a newly identified 112 amino acid hormone, derived as a product of fibronectin type III domain containing 5 (FNDC5), which is highly related to metabolic activity in skeletal muscle and brown fat. The effects of irisin on cardiovascular functions are unknown.
To explore the effects of central and peripheral irisin on cardiovascular functions.
Irisin was either administrated into 3rd ventricle of rats or intravenously, and its effects on blood pressure and cardiac contractibility measured.
Administration of recombinant human irisin into the 3rd brain ventricle of rats activated neurons in the paraventricular nuclei of the hypothalamus. Central administration of irisin increased blood pressure and cardiac contractibility. Exogenous irisin reversed atenolol-induced inhibition of cardiac contractibility. In contrast, peripheral administration of irisin reduced blood pressure in both control and spontaneously hypertensive rats. Irisin dilated mesenteric artery rings through ATP-sensitive potassium channels.
Our studies indicate that central and peripheral irisin may differentially regulate cardiovascular activities.
PMCID: PMC4431576  PMID: 25820670
Irisin; Hypothalamus; Blood pressure; Cardiac contractibility
8.  Investigation of Salivary Function and Oral Microbiota of Radiation Caries-Free People with Nasopharyngeal Carcinoma 
PLoS ONE  2015;10(4):e0123137.
Radiation caries have been reported to be correlated with radiotherapy-induced destruction of salivary function and changes in oral microbiota. There have been no published reports detailing patients who have remained radiation caries-free following radiotherapy for nasopharyngeal carcinoma. The aim of this study was to investigate the relationship between salivary function, oral microbiota and the absence of radiation caries. Twelve radiation caries-free patients and nine patients exhibiting radiation caries following irradiated nasopharyngeal carcinoma were selected. V40, the dose at which the volume of the contralateral parotid gland receives more than 40 Gy, was recorded. Stimulated saliva flow rate, pH values and buffering capacity were examined to assess salivary function. Stimulated saliva was used for molecular profiling by Denaturing Gradient Gel Electrophoresis. Mutans streptococci and Lactobacilli in saliva were also cultivated. There were no significant differences in V40 between radiation caries-free individuals and those with radiation caries. Compared with normal values, the radiation caries-free group had significantly decreased simulated saliva flow rate, while there were no significant differences in the saliva pH value and buffering capacity. Similar results were observed in the radiation caries group. There was no statistical difference in microbial diversity, composition and log CFU counts in cultivation from the radiation caries-free group and the radiation caries group. Eleven genera were detected in these two groups, among which Streptococcus spp. and Neisseria spp. had the highest distribution. Our results suggest that changes in salivary function and in salivary microbiota do not explain the absence of radiation caries in radiation caries-free individuals.
PMCID: PMC4393271  PMID: 25860481
9.  Identification and Functional Analysis of Genome Mutations in a Fluoride-Resistant Streptococcus mutans Strain 
PLoS ONE  2015;10(4):e0122630.
It is known that fluoride-resistant microorganisms are different from fluoride-sensitive ones in growth, adherence and metabolic activity. It was hypothesized that these phenotypic differences were due to stable genotypic changes in the fluoride-resistant strains. However, until now, no studies have reported these genotypic changes. The aim of this study is to identify such changes in a fluoride-resistant Streptococcus mutans strain (C180-2FR) using whole-genome shotgun (WGS) sequencing and to examine the potential function of the identified mutations by comparing gene expression between the fluoride-sensitive (C180-2) and C180-2FR strains. We performed 50 bp paired-end Illumina shotgun sequencing for both strains. Through extensive bioinformatic analysis, we were able to identify 8 single nucleotide polymorphisms (SNPs) in the genome of C180-2FR, which were further confirmed by Sanger sequencing. Expression of the genes containing or in proximity to the SNPs in C180-2 and C180-2FR was then quantified by real-time PCR. A gene cluster containing genes coding for fluoride antiporters was up-regulated 10-fold in C180-2FR when compared to that in C180-2, independent of growth phase. Two SNPs are located in this gene cluster, one in its promoter region and the other in its protein-coding region. In addition, one gene, which codes for a putative glycerol uptake facilitator protein, was found to be down-regulated by 60% in C180-2FR at an early growth phase. The promoter region of this gene contained a SNP. No difference in expression was found for the other SNP-containing genes. In summary, using WGS sequencing, we were able to uncover genetic changes in the genome of a fluoride-resistant strain. These findings can provide new insights into the mechanism of microbial fluoride resistance.
PMCID: PMC4391945  PMID: 25856576
10.  Modulation of food intake by mTOR signaling in the dorsal motor nucleus of vagus in male rats: Focus on ghrelin and nesfatin-1 
Experimental physiology  2013;98(12):10.1113/expphysiol.2013.074930.
Previous studies demonstrate that mTOR signaling in the hypothalamus is involved in the control of energy homeostasis. The aim of this study is to characterize the effect of mTOR signaling in the dorsal motor nucleus of vagus (DMNV) on the energy intake. Phosphor-mTOR was detected in the DMNV neurons and its levels increased by energy deprivation. Rapamycin significantly inhibited mTOR activity and reduced food intake when administrated into 4th ventricle. Exposure of DMNV neurons to ghrelin increased the phosphorylation of mTOR. Fourth ventricle injection of ghrelin significantly increased food intake relative to the control vehicle. Pre-treatment with rapamycin for 15 min attenuated the orexigenic effect of ghrelin. Reduction in the phosphorylation of mTOR was observed following 4th intracerebroventricular injection of nesfatin-1. When administrated by 4th ICV injection, nesfatin-1 suppressed the food intake as compared with the control. The anorexigenic effect of nesfatin-1 was significantly attenuated by pre-treatment with leucine for 15 min. All these studies suggest that mTOR signaling in the DMNV neurons regulates both the nutrient and hormonal signals for the modulation of food intake.
PMCID: PMC3839812  PMID: 23955309
Dorsal vagal complex; ghrelin; nesfatin-1
11.  Oral Microbiota Distinguishes Acute Lymphoblastic Leukemia Pediatric Hosts from Healthy Populations 
PLoS ONE  2014;9(7):e102116.
In leukemia, oral manifestations indicate aberrations in oral microbiota. Microbiota structure is determined by both host and environmental factors. In human hosts, how health status shapes the composition of oral microbiota is largely unknown. Taking advantage of advances in high-throughput sequencing, we compared the composition of supragingival plaque microbiota of acute lymphoblastic leukemia (ALL) pediatric patients with healthy controls. The oral microbiota of leukemia patients had lower richness and less diversity compared to healthy controls. Microbial samples clustered into two major groups, one of ALL patients and another of healthy children, with different structure and composition. Abundance changes of certain taxa including the Phylum Firmicutes, the Class Bacilli, the Order Lactobacillales, the Family Aerococcaceae and Carnobacteriaceae, as well as the Genus Abiotrophia and Granulicatella were associated with leukemia status. ALL patients demonstrated a structural imbalance of the oral microbiota, characterized by reduced diversity and abundance alterations, possibly involved in systemic infections, indicating the importance of immune status in shaping the structure of oral microbiota.
PMCID: PMC4099009  PMID: 25025462
12.  Molecular Characterization of the Microbiota Residing at the Apical Portion of Infected Root Canals of Human Teeth 
Journal of endodontics  2011;37(10):1359-1364.
This study investigated the bacterial communities residing in the apical portion of human teeth with apical periodontitis in primary and secondary infections using a culture-independent molecular biology approach.
Root canal samples from the apical root segments of extracted teeth were collected from 18 teeth with necrotic pulp and 8 teeth with previous endodontic treatment. Samples were processed for amplification via polymerase chain reaction (PCR) and separated with denaturing gradient gel electrophoresis (DGGE). Selected bands were excised from the gel and sequenced for identification.
Comparable to previous studies of entire root canals, the apical bacterial communities in primary infections were significantly more diverse than in secondary infections (p=0.0003). Inter- and intra-patient comparisons exhibited similar variations in profiles. Different roots of the same teeth with secondary infections displayed low similarity in bacterial composition, while an equivalent sample collected from primary infection contained almost identical populations. Sequencing revealed a high prevalence of fusobacteria, Actinomyces sp. and oral Anaeroglobus geminatus in both types of infection. Many secondary infections contained Burkholderiales or Pseudomonas sp. both of which represent opportunistic environmental pathogens.
Certain microorganisms exhibit similar prevalence in primary and secondary infection indicating that they are likely not eradicated during endodontic treatment. The presence of Burkholderiales and Pseudomonas sp. underscores the problem of environmental contamination. Treatment appears to affect the various root canals of multi-rooted teeth differently, resulting in local changes of the microbiota.
PMCID: PMC3415298  PMID: 21924182
Apical periodontitis; endodontic infections; community profiling; polymerase chain reaction; denaturing gradient gel electrophoresis
13.  High-resolution X-ray microdiffraction analysis of natural teeth 
Journal of Synchrotron Radiation  2008;15(Pt 3):235-238.
In situ microzone X-ray diffraction analysis of natural teeth is presented. From our experiment, layer orientation and continuous crystal variations in teeth could be conveniently studied using fast online measurements by high-resolution X-ray microdiffraction equipment.
The main component of natural teeth was determined many years ago as calcium phosphate, mostly in the form of hydroxyapatite with different crystallites. In the past, the method used in tooth crystal investigation has been mainly powder X-ray diffraction analysis, but this method has its drawbacks, i.e. the destruction of the natural tooth structure and the difficulty in examining the preferred orientation in different layers of the tooth. During the last century, microzone X-ray diffraction on the tooth surface was carried out, but, as the technology was less sophisticated, the results obtained were not very detailed. The newly developed microdiffraction equipment permits analysis of the microzone of teeth in situ. To test this new microdiffraction equipment, microdiffraction analysis of one natural healthy deciduous molar tooth and one carious deciduous molar tooth has been performed, using a Bruker D8 instrument. Phase analysis of the two teeth was performed; the crystal size at six test points in the natural healthy tooth was calculated by reflection (211), and the crystal preferred orientation of reflection (300) and reflection (002) at six test points in the natural healthy tooth were compared. The results showed that the tooth was a kind of biological mixed crystal composed of several crystal phases, the main crystal phase being hydroxyapatite. The crystal size grew larger going from the dentin to the enamel. The crystal preferred orientation mainly existed in the enamel, especially in the reflection (002). From our experiment, layer orientation and continuous crystal variations in teeth could be conveniently studied using fast online measurements by high-resolution X-ray microdiffraction equipment.
PMCID: PMC2394821  PMID: 18421147
X-ray microdiffraction; enamel; caries; texture; crystal

Results 1-13 (13)