Lina J Suárez, Roger M Arce, Cristiane Gonçalves, Camila Pinheiro Furquim, Nidia Castro Dos Santos, Belén Retamal‐Valdes, Magda Feres
{"title":"Metronidazole may display anti‐inflammatory features in periodontitis treatment: A scoping review","authors":"Lina J Suárez, Roger M Arce, Cristiane Gonçalves, Camila Pinheiro Furquim, Nidia Castro Dos Santos, Belén Retamal‐Valdes, Magda Feres","doi":"10.1111/omi.12459","DOIUrl":"https://doi.org/10.1111/omi.12459","url":null,"abstract":"AimMetronidazole (MTZ) is an antimicrobial agent used to treat anaerobic infections. It has been hypothesized that MTZ may also have anti‐inflammatory properties, but the evidence is limited and has not been previously reviewed. Thus, this scoping review aimed to answer the following question: “What is the evidence supporting anti‐inflammatory properties of metronidazole that are not mediated by its antimicrobial effects?”MethodsA scoping review was conducted according to the PRISMA‐ScR statement. Five databases were searched up to January 2023 for studies evaluating the anti‐inflammatory properties of MTZ used as monotherapy for treating infectious and inflammatory diseases.ResultsA total of 719 records were identified, and 27 studies (21 in vivo and 6 in vitro) were included. The studies reported experimental evidence of MTZ anti‐inflammatory effects on (1) innate immunity (barrier permeability, leukocyte adhesion, immune cell populations), (2) acquired immunity (lymphocyte proliferation, T‐cell function, cytokine profile), and (3) wound healing/resolution of inflammation.ConclusionTaken together, this scoping review supported a potential anti‐inflammatory effect of MTZ in periodontitis treatment. We recommend that future clinical studies should be conducted to evaluate specific MTZ anti‐inflammatory pathways in the treatment of periodontitis.","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":"58 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tannerella forsythia scavenges Fusobacterium nucleatum secreted NOD2 stimulatory molecules to dampen oral epithelial cell inflammatory response.","authors":"Rajendra P Settem, Angela Ruscitto, Sreedevi Chinthamani, Kiyonobu Honma, Ashu Sharma","doi":"10.1111/omi.12429","DOIUrl":"10.1111/omi.12429","url":null,"abstract":"<p><p>The oral organism Tannerella forsythia is auxotrophic for peptidoglycan amino sugar N-acetylmuramic acid (MurNAc). It survives in the oral cavity by scavenging MurNAc- and MurNAc-linked peptidoglycan fragments (muropeptides) secreted by co-habiting bacteria such as Fusobacterium nucleatum with which it forms synergistic biofilms. Muropeptides, MurNAc-l-Ala-d-isoGln (MDP, muramyl dipeptide) and d-γ-glutamyl-meso-DAP (iE-DAP dipeptide), are strong immunostimulatory molecules that activate nucleotide oligomerization domain (NOD)-like innate immune receptors and induce the expression of inflammatory cytokines and antimicrobial peptides. In this study, we utilized an in vitro T. forsythia-F. nucleatum co-culture model to determine if T. forsythia can selectively scavenge NOD ligands from the environment and impact NOD-mediated inflammation. The results showed that NOD-stimulatory molecules were secreted by F. nucleatum in the spent culture broth, which subsequently induced cytokine and antimicrobial peptide expression in oral epithelial cells. In the spent broth from T. forsythia-F. nucleatum co-cultures, the NOD-stimulatory activity was significantly reduced. These data indicated that F. nucleatum releases NOD2-stimulatory muropeptides in the environment, and T. forsythia can effectively scavenge the muropeptides released by co-habiting bacteria to dampen NOD-mediated host responses. This proof-of-principle study demonstrated that peptidoglycan scavenging by T. forsythia can impact the innate immunity of oral epithelium by dampening NOD activation.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":"40-46"},"PeriodicalIF":2.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10792118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9824215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Scott C Thomas, Yuqi Guo, Fangxi Xu, Deepak Saxena, Xin Li
{"title":"A novel SUCNR1 inhibitor alleviates dysbiosis through inhibition of host responses without direct interaction with host microbiota.","authors":"Scott C Thomas, Yuqi Guo, Fangxi Xu, Deepak Saxena, Xin Li","doi":"10.1111/omi.12431","DOIUrl":"10.1111/omi.12431","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is a chronic metabolic disorder in which insulin resistance and impaired insulin secretion result in altered metabolite balance, specifically elevated levels of circulating glucose and succinate, which increases the risk of many pathologies, including periodontitis. Succinate, a tricarboxylic acid (TCA) cycle intermediate, can be produced and metabolized by both host cells and host microbiota, where elevated levels serve as an inflammation and pathogen threat signal through activating the succinate G protein-coupled receptor, SUCNR1. Modulating succinate-induced SUCNR1 signaling remains a promising therapeutic approach for pathologies resulting in elevated levels of succinate, such as T2D and periodontitis. Here, we demonstrate hyperglycemia and elevated intracellular succinate in a T2D mouse model and determine gut microbiome composition. Drawing on previous work demonstrating the ability of a novel SUCNR1 antagonist, compound 7a, to block inflammation and alleviate dysbiosis in a mouse model, we examined if compound 7a has an impact on the growth and virulence gene expression of bacterial and fungal human microbiota in vitro, and if 7a could reduce bone loss in a periodontitis-induced mouse model. T2D mice harbored a significantly different gut microbiome, suggesting the altered metabolite profile of T2D causes shifts in host-microbial community structure, with enrichment in succinate producers and consumers and mucin-degrading bacteria. Bacterial and fungal cultures showed that 7a did not influence growth or virulence gene expression, suggesting the therapeutic effects of 7a are a direct result of 7a interacting with host cells and that alterations in microbial community structure are driven by reduced host SUCNR1 signaling. This work further suggests that targeting SUCNR1 signaling is a promising therapeutic approach in metabolic, inflammatory, or immune disorders with elevated succinate levels.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":"80-90"},"PeriodicalIF":2.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10266107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicoletta Favale, Roberto Farina, Alberto Carrieri, Anna Simonelli, Mattia Severi, Silvia Sabbioni, Leonardo Trombelli, Chiara Scapoli
{"title":"Functional profile of oral plaque microbiome: Further insight into the bidirectional relationship between type 2 diabetes and periodontitis.","authors":"Nicoletta Favale, Roberto Farina, Alberto Carrieri, Anna Simonelli, Mattia Severi, Silvia Sabbioni, Leonardo Trombelli, Chiara Scapoli","doi":"10.1111/omi.12418","DOIUrl":"10.1111/omi.12418","url":null,"abstract":"<p><p>Increasing evidence support the association between the oral microbiome and human systemic diseases. This association may be attributed to the ability of many oral microbes to influence the inflammatory microenvironment. Herein, we focused our attention on the bidirectional relationship between periodontitis and type 2 diabetes using high-resolution whole metagenomic shotgun analysis to explore the composition and functional profile of the subgingival microbiome in diabetics and non-diabetics subjects with different periodontal conditions. In the present study, the abundance of metabolic pathways encoded by oral microbes was reconstructed from the metagenome, and we identified a set of dysregulated metabolic pathways significantly enriched in the periodontitis and/or diabetic patients. These pathways were mainly involved in branched and aromatic amino acids metabolism, fatty acid biosynthesis and adipocytokine signaling pathways, ferroptosis and iron homeostasis, nucleotide metabolism, and finally in the peptidoglycan and lipopolysaccharides synthesis. Overall, the results of the present study provide evidence in favor of the hypothesis that during the primary inflammatory challenge, regardless of whether it is induced by periodontitis or diabetes, endotoxemia and/or the release of inflammatory cytokines cause a change in precursor and/or in circulating innate immune cells. Dysbiosis and inflammation, also via oral-gut microbiome axis or adipose tissue, reduce the efficacy of the host immune response, while fueling inflammation and can induce that metabolic/epigenetic reprogramming of chromatin accessibility of genes related to the immune response. Moreover, the presence of an enhanced ferroptosis and an imbalance in purine/pyrimidine metabolism provides new insights into the role of ferroptotic death in this comorbidity.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":"62-79"},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9551872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emmanuel Albuquerque-Souza, Benjamin Shelling, Min Jiang, Xia-Juan Xia, Kantapon Rattanaprukskul, Sinem Esra Sahingur
{"title":"Fusobacterium nucleatum triggers senescence phenotype in gingival epithelial cells.","authors":"Emmanuel Albuquerque-Souza, Benjamin Shelling, Min Jiang, Xia-Juan Xia, Kantapon Rattanaprukskul, Sinem Esra Sahingur","doi":"10.1111/omi.12432","DOIUrl":"10.1111/omi.12432","url":null,"abstract":"<p><p>The prevalence of periodontitis increases with physiological aging. However, whether bacteria associated with periodontal diseases foster aging and the mechanisms by which they may do so are unknown. Herein, we hypothesize that Fusobacterium nucleatum, a microorganism associated with periodontitis and several other age-related disorders, triggers senescence, a chief hallmark of aging responsible to reduce tissue repair capacity. Our study analyzed the senescence response of gingival epithelial cells and their reparative capacity upon long-term exposure to F. nucleatum. Specifically, we assessed (a) cell cycle arrest by analyzing the cyclin-dependent kinase inhibitors p16<sup>INK4a</sup> and p14<sup>ARF</sup> and their downstream cascade (pRb, p53, and p21) at both gene and protein levels, (b) lysosomal mediated dysfunction by using assays targeting the expression and activity of the senescence-associated β-galactosidase (SA-β-Gal) enzyme, and (c) nuclear envelope breakdown by assessing the expression of Lamin-B1. The consequences of the senescence phenotype mediated by F. nucleatum were further assessed using wound healing assays. Our results revealed that prolonged exposure to F. nucleatum promotes an aging-like phenotype as evidenced by the increased expression of pro-senescence markers (p16<sup>INK4a</sup> , p21, and pRb) and SA-β-Gal activity and reduced expression of the counter-balancing cascade (p14<sup>ARF</sup> and p53) and Lamin-B1. Furthermore, we also noted impaired wound healing capacity of gingival epithelial cells upon prolong bacterial exposure, which was consistent with the senescence-induced phenotype. Together, our findings provide a proof-of-concept evidence that F. nucleatum triggers a pro-senescence response in gingival epithelial cells. This might affect periodontal tissue homeostasis by reducing its repair capacity and, consequently, increasing susceptibility to periodontitis during aging.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":"29-39"},"PeriodicalIF":2.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10339538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"GroEL of Porphyromonas gingivalis-induced microRNAs accelerate tumor neovascularization by downregulating thrombomodulin expression in endothelial progenitor cells.","authors":"Feng-Yen Lin, Yi-Ting Tsai, Chun-Yao Huang, Ze-Hao Lai, Chien-Sung Tsai, Chun-Ming Shih, Cheng-Yen Lin, Yi-Wen Lin","doi":"10.1111/omi.12415","DOIUrl":"10.1111/omi.12415","url":null,"abstract":"<p><p>We found that GroEL in Porphyromonas gingivalis accelerated tumor growth and increased mortality in tumor-bearing mice; GroEL promoted proangiogenic function, which may be the reason for promoting tumor growth. To understand the regulatory mechanisms by which GroEL increases the proangiogenic function of endothelial progenitor cells (EPCs), we explored in this study. In EPCs, MTT assay, wound-healing assay, and tube formation assay were performed to analyze its activity. Western blot and immunoprecipitation were used to study the protein expression along with next-generation sequencing for miRNA expression. Finally, a murine tumorigenesis animal model was used to confirm the results of in vitro. The results indicated that thrombomodulin (TM) direct interacts with PI<sub>3</sub> K/Akt to inhibit the activation of signaling pathways. When the expression of TM is decreased by GroEL stimulation, molecules in the PI<sub>3</sub> K/Akt signaling axis are released and activated, resulting in increased migration and tube formation of EPCs. In addition, GroEL inhibits TM mRNA expression by activating miR-1248, miR-1291, and miR-5701. Losing the functions of miR-1248, miR-1291, and miR-5701 can effectively alleviate the GroEL-induced decrease in TM protein levels and inhibit the proangiogenic abilities of EPCs. These results were also confirmed in animal experiments. In conclusion, the intracellular domain of the TM of EPCs plays a negative regulatory role in the proangiogenic capabilities of EPCs, mainly through direct interaction between TM and PI<sub>3</sub> K/Akt to inhibit the activation of signaling pathways. The effects of GroEL on tumor growth can be reduced by inhibiting the proangiogenic properties of EPCs through the inhibition of the expression of specific miRNAs.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":"47-61"},"PeriodicalIF":2.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9474999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Porphyromonas gingivalis GroEL exacerbates orthotopic allograft transplantation vasculopathy via impairment of endothelial cell function.","authors":"Chien-Sung Tsai, Chun-Yao Huang, Yi-Ting Tsai, Chun-Ming Shih, Ze-Hao Lai, Chen-Wei Liu, Yi-Wen Lin, Feng-Yen Lin","doi":"10.1111/omi.12453","DOIUrl":"https://doi.org/10.1111/omi.12453","url":null,"abstract":"<p><p>Orthotopic allograft transplantation (OAT) is a significant approach to addressing organ failure. However, persistent immune responses to the allograft affect chronic rejection, which induces OAT vasculopathy (OATV) and organ failure. Porphyromonas gingivalis can infiltrate remote organs via the bloodstream, thereby intensifying the severity of cardiovascular, respiratory, and neurodegenerative diseases and cancer. GroEL, a virulence factor of P. gingivalis promotes pro-inflammatory cytokine production in host cells, which assumes to play a pivotal role in the pathogenesis of cardiovascular diseases. Although the aggravation of OATV is attributable to numerous factors, the role of GroEL remains ambiguous. Therefore, this study aimed to investigate the impact of GroEL on OATV. Aortic grafts extracted from PVG/Seac rats were transplanted into ACI/NKyo rats and in vitro human endothelial progenitor cell (EPC) and coronary artery endothelial cell (HCAEC) models. The experimental findings revealed that GroEL exacerbates OATV in ACI/NKyo rats by affecting EPC and smooth muscle progenitor cell (SMPC) function and enabling the anomalous accumulation of collagen. In vitro, GroEL spurs endothelial-mesenchymal transition in EPCs, reduces HCAEC tube formation and barrier function by downregulating junction proteins, accelerates HCAEC aging by lowering mitochondrial membrane potential and respiratory function, and impedes HCAEC migration by modulating cytoskeleton-associated molecules. This study suggests that P. gingivalis GroEL could potentially augment OATV by impacting vascular progenitor and endothelial cell functions.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139681308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arunima Mishra, Yuetan Dou, Charles Wang, Hansel M Fletcher
{"title":"Filifactor alocis enhances survival of Porphyromonas gingivalis W83 in response to H<sub>2</sub> O<sub>2</sub> -induced stress.","authors":"Arunima Mishra, Yuetan Dou, Charles Wang, Hansel M Fletcher","doi":"10.1111/omi.12445","DOIUrl":"10.1111/omi.12445","url":null,"abstract":"<p><p>A dysbiotic microbial community whose members have specific/synergistic functions that are modulated by environmental conditions, can disturb homeostasis in the subgingival space leading to destructive inflammation, plays a role in the progression of periodontitis. Filifactor alocis, a gram-positive, anaerobic bacterium, is a newly recognized microbe that shows a strong correlation with periodontal disease. Our previous observations suggested F. alocis to be more resistant to oxidative stress compared to Porphyromonas gingivalis. The objective of this study is to further determine if F. alocis, because of its increased resistance to oxidative stress, can affect the survival of other 'established' periodontal pathogens under environmental stress conditions typical of the periodontal pocket. Here, we have shown that via their interaction, F. alocis protects P. gingivalis W83 under H<sub>2</sub> O<sub>2</sub> -induced oxidative stress conditions. Transcriptional profiling of the interaction of F. alocis and P. gingivalis in the presence of H<sub>2</sub> O<sub>2</sub> -induced stress revealed the modulation of several genes, including those with ABC transporter and other cellular functions. The ABC transporter operon (PG0682-PG0685) of P. gingivalis was not significant to its enhanced survival when cocultured with F. alocis under H<sub>2</sub> O<sub>2</sub> -induced oxidative stress. In F. alocis, one of the most highly up-regulated operons (FA0894-FA0897) is predicted to encode a putative manganese ABC transporter, which in other bacteria can play an essential role in oxidative stress protection. Collectively, the results may indicate that F. alocis could likely stabilize the microbial community in the inflammatory microenvironment of the periodontal pocket by reducing the oxidative environment. This strategy could be vital to the survival of other pathogens, such as P. gingivalis, and its ability to adapt and persist in the periodontal pocket.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":"12-26"},"PeriodicalIF":2.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10842171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138470526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David R Danforth, Marcella Melloni, Richard Thorpe, Avi Cohen, Richard Voogt, Jake Tristano, Keith P Mintz
{"title":"Dual function of the O-antigen WaaL ligase of Aggregatibacter actinomycetemcomitans.","authors":"David R Danforth, Marcella Melloni, Richard Thorpe, Avi Cohen, Richard Voogt, Jake Tristano, Keith P Mintz","doi":"10.1111/omi.12444","DOIUrl":"10.1111/omi.12444","url":null,"abstract":"<p><p>Protein glycosylation is critical to the quaternary structure and collagen-binding activity of the extracellular matrix protein adhesin A (EmaA) associated with Aggregatibacter actinomycetemcomitans. The glycosylation of this large, trimeric autotransporter adhesin is postulated to be mediated by WaaL, an enzyme with the canonical function to ligate the O-polysaccharide (O-PS) antigen with a terminal sugar of the lipid A-core oligosaccharide of lipopolysaccharide (LPS). In this study, we have determined that the Escherichia coli waaL ortholog (rflA) does not restore collagen binding of a waaL mutant strain of A. actinomycetemcomitans but does restore O-PS ligase activity following transformation of a plasmid expressing waaL. Therefore, a heterologous E. coli expression system was developed constituted of two independently replicating plasmids expressing either waaL or emaA of A. actinomycetemcomitans to directly demonstrate the necessity of ligase activity for EmaA collagen binding. Proper expression of the protein encoded by each plasmid was characterized, and the individually transformed strains did not promote collagen binding. However, coexpression of the two plasmids resulted in a strain with a significant increase in collagen binding activity and a change in the biochemical properties of the protein. These results provide additional data supporting the novel hypothesis that the WaaL ligase of A. actinomycetemcomitans shares a dual role as a ligase in LPS biosynthesis and is required for collagen binding activity of EmaA.</p>","PeriodicalId":18815,"journal":{"name":"Molecular Oral Microbiology","volume":" ","pages":"471-488"},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10758912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71522141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}