Background:Benign prostatic hyperplasia(BPH)is the most common disease in elderly men.There is increasing evidence that periodontitis increases the risk of BPH,but the specific mechanism remains unclear.This study aim...Background:Benign prostatic hyperplasia(BPH)is the most common disease in elderly men.There is increasing evidence that periodontitis increases the risk of BPH,but the specific mechanism remains unclear.This study aimed to explore the role and mechanism of the key periodontal pathogen Porphyromonas gingivalis(P.gingivalis)in the development of BPH.Methods:The subgingival plaque(Sp)and prostatic fluid(Pf)of patients with BPH concurrent periodontitis were extracted and cultured for 16S r DNA sequencing.Ligature-induced periodontitis,testosterone-induced BPH and the composite models in rats were established.The P.gingivalis and its toxic factor P.gingivalis lipopolysaccharide(P.gLPS)were injected into the ventral lobe of prostate in rats to simulate its colonization of prostate.P.g-LPS was used to construct the prostate cell infection model for mechanism exploration.Results:P.gingivalis,Streptococcus oralis,Capnocytophaga ochracea and other oral pathogens were simultaneously detected in the Sp and Pf of patients with BPH concurrent periodontitis,and the average relative abundance of P.gingivalis was found to be the highest.P.gingivalis was detected in both Sp and Pf in 62.5%of patients.Simultaneous periodontitis and BPH synergistically aggravated prostate histological changes.P.gingivalis and P.gLPS infection could induce obvious hyperplasia of the prostate epithelium and stroma(epithelial thickness was 2.97-fold and 3.08-fold that of control group,respectively),and increase of collagen fibrosis(3.81-fold and 5.02-fold that of control group,respectively).P.gingivalis infection promoted prostate cell proliferation,inhibited apoptosis,and upregulated the expression of inflammatory cytokines interleukin-6(IL-6;4.47-fold),interleukin-6 receptor-α(IL-6Rα;5.74-fold)and glycoprotein 130(gp130;4.47-fold)in prostatic tissue.P.g-LPS could significantly inhibit cell apoptosis,promote mitosis and proliferation of cells.P.g-LPS activates the Akt pathway through IL-6/IL-6Rα/gp130 complex,which destroys the imbalance between proliferation and apoptosis of prostate cells,induces BPH.Conclusion:P.gingivalis was abundant in the Pf of patients with BPH concurrent periodontitis.P.gingivalis infection can promote BPH,which may affect the progression of BPH via inflammation and the Akt signaling pathway.展开更多
[Objectives]To investigate the ameliorative effects of Huanglian Jiedu Decoction(HLJDD)on cognitive function impairment in an Alzheimer s disease(AD)mouse model induced by Porphyromonas gingivalis infection.[Methods]T...[Objectives]To investigate the ameliorative effects of Huanglian Jiedu Decoction(HLJDD)on cognitive function impairment in an Alzheimer s disease(AD)mouse model induced by Porphyromonas gingivalis infection.[Methods]Thirty-six male C57BL/6 mice were randomly assigned to six groups:control group,model group,low-dose HLJDD group,medium-dose HLJDD group,high-dose HLJDD group,and positive drug group(treated with moxifloxacin).With the exception of the control group,all groups underwent an 8-week P.gingivalis chronic infection model induced via oral administration.Subsequently,each treatment group received corresponding doses of HLJDD(2.5,5,and 10 mg/g)or moxifloxacin for 8 weeks intervention.The novel object recognition test was employed to evaluate the non-spatial memory abilities of mice,and the novel object exploration preference index was calculated to assess cognitive function.[Results]Compared to the control group,the novel object exploration preference index of mice in the model group was significantly reduced(P<0.01),indicating that P.gingivalis infection effectively induced cognitive impairment.Relative to the model group,mice treated with medium and high doses of HLJDD exhibited a significant,dose-dependent increase in the novel object exploration preference index,whereas the low-dose group showed no significant improvement.Additionally,the positive drug moxifloxacin demonstrated a significant neuroprotective effect on cognition.[Conclusions]HLJDD effectively improves cognitive function impairment in AD model mice induced by P.gingivalis infection,offering novel experimental evidence supporting the heat-clearing and detoxification approach as well as the therapeutic potential of traditional Chinese medicine(TCM)compounds in the intervention of AD.展开更多
Cancer stem cells(CSCs)are widely acknowledged as primary mediators to the initiation and progression of tumors.The association between microbial infection and cancer stemness has garnered considerable scholarly inter...Cancer stem cells(CSCs)are widely acknowledged as primary mediators to the initiation and progression of tumors.The association between microbial infection and cancer stemness has garnered considerable scholarly interest in recent years.Porphyromonas gingivalis(P.gingivalis)is increasingly considered to be closely related to the development of oral squamous cell carcinoma(OSCC).Nevertheless,the role of P.gingivalis in the stemness of OSCC cells remains uncertain.Herein,we showed that P.gingivalis was positively correlated with CSC markers expression in human OSCC specimens,promoted the stemness and tumorigenicity of OSCC cells,and enhanced tumor formation in nude mice.Mechanistically,P.gingivalis increased lipid synthesis in OSCC cells by upregulating the expression of stearoyl-CoA desaturase 1(SCD1)expression,a key enzyme involved in lipid metabolism,which ultimately resulted in enhanced acquisition of stemness.Moreover,SCD1 suppression attenuated P.gingivalis-induced stemness of OSCC cells,including CSCs markers expression,sphere formation ability,chemoresistance,and tumor growth,in OSCC cells both in vitro and in vivo.Additionally,upregulation of SCD1 in P.gingivalis-infected OSCC cells was associated with the expression of KLF5,and that was modulated by P.gingivalis-activated NOD1 signaling.Taken together,these findings highlight the importance of SCD1-dependent lipid synthesis in P.gingivalis-induced stemness acquisition in OSCC cells,suggest that the NOD1/KLF5 axis may play a key role in regulating SCD1 expression and provide a molecular basis for targeting SCD1 as a new option for attenuating OSCC cells stemness.展开更多
BACKGROUND Alzheimer's disease is a neurodegenerative dementia characterized by accumulation ofβ-amyloid plaques,tau hyperphosphorylation,and neuroinflammation.Recent research has highlighted a potential relation...BACKGROUND Alzheimer's disease is a neurodegenerative dementia characterized by accumulation ofβ-amyloid plaques,tau hyperphosphorylation,and neuroinflammation.Recent research has highlighted a potential relationship between chronic oral infections and neurodegeneration,particularly the involvement of Porphyromonas gingivalis(P.gingivalis),a key pathogen in periodontitis.Experimental mouse models have been used to explore how P.gingivalis products contribute to neuroinflammatory and degenerative processes.However,a comprehensive synthesis of these findings is lacking.This systematic review evaluates the role of P.gingivalisderived factors in triggering Alzheimer's-like pathology,with an emphasis on bacterial products and host immune responses.We hypothesize that P.gingivalis products exacerbate neuroinflammation and pathology in mouse models of Alzheimer's disease.AIM To link gingival P.gingivalis bacteria-associated products with the onset and progression of Alzheimer's disease-like pathology in mouse models.METHODS This systematic review followed the 2020 PRISMA guidelines.A comprehensive search was conducted in five databases(PubMed,Scopus,ScienceDirect,Sage,SpringerLink)for original studies between 2014 and 2024.Studies included mouse models to evaluate the effect of P.gingivalis or its products on Alzheimer's-like pathologies.Exclusion criteria were in vitro,human,or review studies.Twenty-three studies met the inclusion criteria.Bacterial components and activated host factors were extracted,categorized,and analyzed using narrative synthesis and descriptive statistics.RESULTS In 24 studies,lipopolysaccharides(54.84%)and gingipains(25.81%)were the most frequently reported P.gingivalis products.These factors activated toll-like receptors(TLR2/TLR4),microglia,and astrocytes,increasing levels of interleukin 1 beta,tumor necrosis factor-alpha,and other proinflammatory cytokines.The host response includedβ-amyloid accumulation,Tau hyperphosphorylation,and changes in blood-brain barrier permeability.Glial cells were the most frequently mentioned host factors(n=15),followed by proteins(n=13)and cytokines(n=11).These interactions promoted cognitive impairment,synaptic dysfunction,and neurodegeneration in mouse models,supporting a role for P.gingivalis in Alzheimer's-like pathology.CONCLUSION P.gingivalis products induce neuroinflammatory responses and Alzheimer's-like pathology in mouse models,supporting their role as contributors to neurodegeneration and potential targets for preventive strategies.展开更多
Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology i...Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.展开更多
Periodontal disease has been recently linked to a variety of systemic conditions such as diabetes, cardiovascular disease, preterm delivery, and oral cancer. The most common bacteria associated with periodontal diseas...Periodontal disease has been recently linked to a variety of systemic conditions such as diabetes, cardiovascular disease, preterm delivery, and oral cancer. The most common bacteria associated with periodontal disease, Porphyromonas gingivalis （P. gingivalis） has not yet been studied in the malignant gingival tissues. The objective of this study was to investigate the presence of R gingivalis in specimens from squamous cell carcinoma patients. We have performed immunohistochemical staining to investigate the presence of R gingivafis and Streptococcus gordonii （S. gordonii）, a non invasive oral bacteria, in paraffin embedded samples of gingival squamous cell carcinoma （n=10） and normal gingiva （n=5）. Staining for R gingivalis revealed the presence of the bacteria in normal gingival tissues and gingival carcinoma, with higher levels （more than 33%, P〈0.05） detected in the carcinoma samples. The staining intensity was also significantly enhanced in the malignant tissue by 2 folds （P〈0.023） compared to specimens stained for the non-invasive S. gordonii. R gingivalis is abundantly present in malignant oral epithelium suggesting a potential association of the bacteria with gingival squamous cell carcinoma.展开更多
Porphyromonas gingivalis(P. gingivalis) is an anaerobic gram-negative bacterium that colonizes in the epithelium and has been strongly associated with periodontal disease. Recently, various degrees of associations bet...Porphyromonas gingivalis(P. gingivalis) is an anaerobic gram-negative bacterium that colonizes in the epithelium and has been strongly associated with periodontal disease. Recently, various degrees of associations between P.gingivalis and digestive system cancers, including oral squamous cell carcinoma in the oral cavity, oesophageal squamous carcinoma in the digestive tract, and pancreatic cancer in pancreatic tissues, have been displayed in multiple clinical and experimental studies. Since P. gingivalis has a strong association with periodontal diseases, not only the relationships between P. gingivalis and digestive system tumours but also the effects induced by periodontal diseases on cancers are well-illustrated in this review. In addition, the prevention and possible treatments for these digestive system tumours induced by P. gingivalis infection are also included in this review. At the end, we also highlighted the possible mechanisms of cancers caused by P. gingivalis. One important carcinogenic effect of P. gingivalis is inhibiting the apoptosis of epithelial cells,which also plays an intrinsic role in protecting cancerous cells. Some signalling pathways activated by P. gingivalis are involved in cell apoptosis, tumourigenesis,immune evasion and cell invasion of tumour cells. In addition, metabolism of potentially carcinogenic substances caused by P. gingivalis is also one of the connections between this bacterium and cancers.展开更多
Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer’s...Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer’s disease(AD). The blood-brain barrier(BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1(Cav-1) expression was enhanced after P. gingivalis infection.Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain(RgpA) were detected.Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a(Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.展开更多
Porphyromonas gingivalis(P.gingivalis),a key pathogen in periodontitis,has been shown to accelerate the progression of atherosclerosis(AS).However,the definite mechanisms remain elusive.Emerging evidence supports an a...Porphyromonas gingivalis(P.gingivalis),a key pathogen in periodontitis,has been shown to accelerate the progression of atherosclerosis(AS).However,the definite mechanisms remain elusive.Emerging evidence supports an association between mitochondrial dysfunction and AS.In our study,the impact of P.gingivalis on mitochondrial dysfunction and the potential mechanism were investigated.The mitochondrial morphology of EA.hy926 cells infected with P.gingivalis was assessed by transmission electron microscopy,mitochondrial staining,and quantitative analysis of the mitochondrial network.Fluorescence staining and flow cytometry analysis were performed to determine mitochondrial reactive oxygen species(mtROS)and mitochondrial membrane potential(MMP)levels.Cellular ATP production was examined by a luminescence assay kit.The expression of key fusion and fission proteins was evaluated by western blot and immunofluorescence.Mdivi-1,a specific Drp1 inhibitor,was used to elucidate the role of Drp1 in mitochondrial dysfunction.Our findings showed that P.gingivalis infection induced mitochondrial fragmentation,increased the mtROS levels,and decreased the MMP and ATP concentration in vascular endothelial cells.We observed upregulation of Drp1(Ser616)phosphorylation and translocation of Drp1 to mitochondria.Mdivi-1 blocked the mitochondrial fragmentation and dysfunction induced by P.gingivalis.Collectively,these results revealed that P.gingivalis infection promoted mitochondrial fragmentation and dysfunction,which was dependent on Drp1.Mitochondrial dysfunction may represent the mechanism by which P.gingivalis exacerbates atherosclerotic lesions.展开更多
Cardiovascular disease is still the leading cause of mortality worldwide.Vascular endothelial dysfunction is viewed as the initial step of most cardiovascular diseases.Many studies have indicated that periodontal path...Cardiovascular disease is still the leading cause of mortality worldwide.Vascular endothelial dysfunction is viewed as the initial step of most cardiovascular diseases.Many studies have indicated that periodontal pathogens,especially Porphyromonas gingivalis,are closely correlated with vascular endothelial homeostasis,but the function of P.gingivalis and the underlying mechanisms are still elusive.To illuminate the effects and elucidate the mechanisms of P.gingivalis on endothelial structural integrity,we developed P.gingivalis infection models in vivo and in vitro.Endothelial cell proliferation,differentiation and apoptosis were detected.Here,we showed that P.gingivalis can impair endothelial integrity by inhibiting cell proliferation and inducing endothelial mesenchymal transformation and apoptosis of endothelial cells,which reduce the cell levels and cause the endothelium to lose its ability to repair itself.A mechanistic analysis showed that TLR antagonist or NF-κB signalling inhibitor can largely rescue the damaged integrity of the endothelium caused by P.gingivalis,suggesting that TLR-NF-κB signalling plays a vital role in vascular endothelial homeostasis destroyed by P.gingivalis.These results suggest a potential intervention method for the prevention and treatment of cardiovascular disease.展开更多
基金supported(in part)by the National Natural Science Foundation of China(82200862,82370778)the Hubei Provincial Natural Science Foundation(2022CFB681,2023AFA061,2019CFB760)+4 种基金the Hubei Province Health and Family Planning Scientific Research Project(WJ2023M058,WJ2019H035)the Key Scientific Research Project of Education Department of Henan Province(22A320038)the Fundamental Research Funds for the Central Universities(2042023kf1019,2042023kf0051,2042022kf0072)the Zhongnan Hospital of Wuhan University,Science Technology and Innovation Seed Fund(CXPY2022074)the Young Top-notch Talent Cultivation Program of Hubei Province(for Prof.Zeng XT).
文摘Background:Benign prostatic hyperplasia(BPH)is the most common disease in elderly men.There is increasing evidence that periodontitis increases the risk of BPH,but the specific mechanism remains unclear.This study aimed to explore the role and mechanism of the key periodontal pathogen Porphyromonas gingivalis(P.gingivalis)in the development of BPH.Methods:The subgingival plaque(Sp)and prostatic fluid(Pf)of patients with BPH concurrent periodontitis were extracted and cultured for 16S r DNA sequencing.Ligature-induced periodontitis,testosterone-induced BPH and the composite models in rats were established.The P.gingivalis and its toxic factor P.gingivalis lipopolysaccharide(P.gLPS)were injected into the ventral lobe of prostate in rats to simulate its colonization of prostate.P.g-LPS was used to construct the prostate cell infection model for mechanism exploration.Results:P.gingivalis,Streptococcus oralis,Capnocytophaga ochracea and other oral pathogens were simultaneously detected in the Sp and Pf of patients with BPH concurrent periodontitis,and the average relative abundance of P.gingivalis was found to be the highest.P.gingivalis was detected in both Sp and Pf in 62.5%of patients.Simultaneous periodontitis and BPH synergistically aggravated prostate histological changes.P.gingivalis and P.gLPS infection could induce obvious hyperplasia of the prostate epithelium and stroma(epithelial thickness was 2.97-fold and 3.08-fold that of control group,respectively),and increase of collagen fibrosis(3.81-fold and 5.02-fold that of control group,respectively).P.gingivalis infection promoted prostate cell proliferation,inhibited apoptosis,and upregulated the expression of inflammatory cytokines interleukin-6(IL-6;4.47-fold),interleukin-6 receptor-α(IL-6Rα;5.74-fold)and glycoprotein 130(gp130;4.47-fold)in prostatic tissue.P.g-LPS could significantly inhibit cell apoptosis,promote mitosis and proliferation of cells.P.g-LPS activates the Akt pathway through IL-6/IL-6Rα/gp130 complex,which destroys the imbalance between proliferation and apoptosis of prostate cells,induces BPH.Conclusion:P.gingivalis was abundant in the Pf of patients with BPH concurrent periodontitis.P.gingivalis infection can promote BPH,which may affect the progression of BPH via inflammation and the Akt signaling pathway.
基金Supported by National Natural Science Foundation of China(82160832)Natural Science Foundation of Guangxi Zhuang Autonomous Region(2017GXNS-FAA198255)+2 种基金Open Project of Guangxi Key Laboratory of Brain and Cognitive Neuroscience(GKLBCN-202206-02)Guangxi Undergraduate Innovation and Entrepreneurship Training Program(202410601029,S202410601113)The 4th Thousand Young and Middle-Aged Backbone Teachers Cultivation Program of Guangxi Higher Education Institutions.
文摘[Objectives]To investigate the ameliorative effects of Huanglian Jiedu Decoction(HLJDD)on cognitive function impairment in an Alzheimer s disease(AD)mouse model induced by Porphyromonas gingivalis infection.[Methods]Thirty-six male C57BL/6 mice were randomly assigned to six groups:control group,model group,low-dose HLJDD group,medium-dose HLJDD group,high-dose HLJDD group,and positive drug group(treated with moxifloxacin).With the exception of the control group,all groups underwent an 8-week P.gingivalis chronic infection model induced via oral administration.Subsequently,each treatment group received corresponding doses of HLJDD(2.5,5,and 10 mg/g)or moxifloxacin for 8 weeks intervention.The novel object recognition test was employed to evaluate the non-spatial memory abilities of mice,and the novel object exploration preference index was calculated to assess cognitive function.[Results]Compared to the control group,the novel object exploration preference index of mice in the model group was significantly reduced(P<0.01),indicating that P.gingivalis infection effectively induced cognitive impairment.Relative to the model group,mice treated with medium and high doses of HLJDD exhibited a significant,dose-dependent increase in the novel object exploration preference index,whereas the low-dose group showed no significant improvement.Additionally,the positive drug moxifloxacin demonstrated a significant neuroprotective effect on cognition.[Conclusions]HLJDD effectively improves cognitive function impairment in AD model mice induced by P.gingivalis infection,offering novel experimental evidence supporting the heat-clearing and detoxification approach as well as the therapeutic potential of traditional Chinese medicine(TCM)compounds in the intervention of AD.
基金supported by the National Natural Science Foundation of China(grant#82370975 and 82170969)。
文摘Cancer stem cells(CSCs)are widely acknowledged as primary mediators to the initiation and progression of tumors.The association between microbial infection and cancer stemness has garnered considerable scholarly interest in recent years.Porphyromonas gingivalis(P.gingivalis)is increasingly considered to be closely related to the development of oral squamous cell carcinoma(OSCC).Nevertheless,the role of P.gingivalis in the stemness of OSCC cells remains uncertain.Herein,we showed that P.gingivalis was positively correlated with CSC markers expression in human OSCC specimens,promoted the stemness and tumorigenicity of OSCC cells,and enhanced tumor formation in nude mice.Mechanistically,P.gingivalis increased lipid synthesis in OSCC cells by upregulating the expression of stearoyl-CoA desaturase 1(SCD1)expression,a key enzyme involved in lipid metabolism,which ultimately resulted in enhanced acquisition of stemness.Moreover,SCD1 suppression attenuated P.gingivalis-induced stemness of OSCC cells,including CSCs markers expression,sphere formation ability,chemoresistance,and tumor growth,in OSCC cells both in vitro and in vivo.Additionally,upregulation of SCD1 in P.gingivalis-infected OSCC cells was associated with the expression of KLF5,and that was modulated by P.gingivalis-activated NOD1 signaling.Taken together,these findings highlight the importance of SCD1-dependent lipid synthesis in P.gingivalis-induced stemness acquisition in OSCC cells,suggest that the NOD1/KLF5 axis may play a key role in regulating SCD1 expression and provide a molecular basis for targeting SCD1 as a new option for attenuating OSCC cells stemness.
文摘BACKGROUND Alzheimer's disease is a neurodegenerative dementia characterized by accumulation ofβ-amyloid plaques,tau hyperphosphorylation,and neuroinflammation.Recent research has highlighted a potential relationship between chronic oral infections and neurodegeneration,particularly the involvement of Porphyromonas gingivalis(P.gingivalis),a key pathogen in periodontitis.Experimental mouse models have been used to explore how P.gingivalis products contribute to neuroinflammatory and degenerative processes.However,a comprehensive synthesis of these findings is lacking.This systematic review evaluates the role of P.gingivalisderived factors in triggering Alzheimer's-like pathology,with an emphasis on bacterial products and host immune responses.We hypothesize that P.gingivalis products exacerbate neuroinflammation and pathology in mouse models of Alzheimer's disease.AIM To link gingival P.gingivalis bacteria-associated products with the onset and progression of Alzheimer's disease-like pathology in mouse models.METHODS This systematic review followed the 2020 PRISMA guidelines.A comprehensive search was conducted in five databases(PubMed,Scopus,ScienceDirect,Sage,SpringerLink)for original studies between 2014 and 2024.Studies included mouse models to evaluate the effect of P.gingivalis or its products on Alzheimer's-like pathologies.Exclusion criteria were in vitro,human,or review studies.Twenty-three studies met the inclusion criteria.Bacterial components and activated host factors were extracted,categorized,and analyzed using narrative synthesis and descriptive statistics.RESULTS In 24 studies,lipopolysaccharides(54.84%)and gingipains(25.81%)were the most frequently reported P.gingivalis products.These factors activated toll-like receptors(TLR2/TLR4),microglia,and astrocytes,increasing levels of interleukin 1 beta,tumor necrosis factor-alpha,and other proinflammatory cytokines.The host response includedβ-amyloid accumulation,Tau hyperphosphorylation,and changes in blood-brain barrier permeability.Glial cells were the most frequently mentioned host factors(n=15),followed by proteins(n=13)and cytokines(n=11).These interactions promoted cognitive impairment,synaptic dysfunction,and neurodegeneration in mouse models,supporting a role for P.gingivalis in Alzheimer's-like pathology.CONCLUSION P.gingivalis products induce neuroinflammatory responses and Alzheimer's-like pathology in mouse models,supporting their role as contributors to neurodegeneration and potential targets for preventive strategies.
基金funded by grants from the National Natural Science Foundation of China(grant numbers 82170912 and 82370910)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(No.YSP202404).
文摘Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.
基金supported by National Institute of Health/National Institute of Dental and Craniofacial Research training grant T32DE007200
文摘Periodontal disease has been recently linked to a variety of systemic conditions such as diabetes, cardiovascular disease, preterm delivery, and oral cancer. The most common bacteria associated with periodontal disease, Porphyromonas gingivalis （P. gingivalis） has not yet been studied in the malignant gingival tissues. The objective of this study was to investigate the presence of R gingivalis in specimens from squamous cell carcinoma patients. We have performed immunohistochemical staining to investigate the presence of R gingivafis and Streptococcus gordonii （S. gordonii）, a non invasive oral bacteria, in paraffin embedded samples of gingival squamous cell carcinoma （n=10） and normal gingiva （n=5）. Staining for R gingivalis revealed the presence of the bacteria in normal gingival tissues and gingival carcinoma, with higher levels （more than 33%, P〈0.05） detected in the carcinoma samples. The staining intensity was also significantly enhanced in the malignant tissue by 2 folds （P〈0.023） compared to specimens stained for the non-invasive S. gordonii. R gingivalis is abundantly present in malignant oral epithelium suggesting a potential association of the bacteria with gingival squamous cell carcinoma.
基金Supported by Changzhou High-Level Medical Talents Training Project,No:2016ZCLJ002
文摘Porphyromonas gingivalis(P. gingivalis) is an anaerobic gram-negative bacterium that colonizes in the epithelium and has been strongly associated with periodontal disease. Recently, various degrees of associations between P.gingivalis and digestive system cancers, including oral squamous cell carcinoma in the oral cavity, oesophageal squamous carcinoma in the digestive tract, and pancreatic cancer in pancreatic tissues, have been displayed in multiple clinical and experimental studies. Since P. gingivalis has a strong association with periodontal diseases, not only the relationships between P. gingivalis and digestive system tumours but also the effects induced by periodontal diseases on cancers are well-illustrated in this review. In addition, the prevention and possible treatments for these digestive system tumours induced by P. gingivalis infection are also included in this review. At the end, we also highlighted the possible mechanisms of cancers caused by P. gingivalis. One important carcinogenic effect of P. gingivalis is inhibiting the apoptosis of epithelial cells,which also plays an intrinsic role in protecting cancerous cells. Some signalling pathways activated by P. gingivalis are involved in cell apoptosis, tumourigenesis,immune evasion and cell invasion of tumour cells. In addition, metabolism of potentially carcinogenic substances caused by P. gingivalis is also one of the connections between this bacterium and cancers.
基金supported by Scientific Research Funding Project of Education Department of Liaoning Province [grant number LJKZ0782]National Natural Science Foundation of China [grant numbers 81670999]。
文摘Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer’s disease(AD). The blood-brain barrier(BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1(Cav-1) expression was enhanced after P. gingivalis infection.Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain(RgpA) were detected.Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a(Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.
基金supported by grants from National Natural Science Foundation of China(NO.81970943,81870771)。
文摘Porphyromonas gingivalis(P.gingivalis),a key pathogen in periodontitis,has been shown to accelerate the progression of atherosclerosis(AS).However,the definite mechanisms remain elusive.Emerging evidence supports an association between mitochondrial dysfunction and AS.In our study,the impact of P.gingivalis on mitochondrial dysfunction and the potential mechanism were investigated.The mitochondrial morphology of EA.hy926 cells infected with P.gingivalis was assessed by transmission electron microscopy,mitochondrial staining,and quantitative analysis of the mitochondrial network.Fluorescence staining and flow cytometry analysis were performed to determine mitochondrial reactive oxygen species(mtROS)and mitochondrial membrane potential(MMP)levels.Cellular ATP production was examined by a luminescence assay kit.The expression of key fusion and fission proteins was evaluated by western blot and immunofluorescence.Mdivi-1,a specific Drp1 inhibitor,was used to elucidate the role of Drp1 in mitochondrial dysfunction.Our findings showed that P.gingivalis infection induced mitochondrial fragmentation,increased the mtROS levels,and decreased the MMP and ATP concentration in vascular endothelial cells.We observed upregulation of Drp1(Ser616)phosphorylation and translocation of Drp1 to mitochondria.Mdivi-1 blocked the mitochondrial fragmentation and dysfunction induced by P.gingivalis.Collectively,these results revealed that P.gingivalis infection promoted mitochondrial fragmentation and dysfunction,which was dependent on Drp1.Mitochondrial dysfunction may represent the mechanism by which P.gingivalis exacerbates atherosclerotic lesions.
基金This work was supported by the National Science Foundation for Distinguished Young Scholars of China(31725011 to Lili Chen)Young Scientists of China(81800986 to Qingming Tang)the Chinese Stomatological Association(CSAZ2015-01 to Lili Chen).
文摘Cardiovascular disease is still the leading cause of mortality worldwide.Vascular endothelial dysfunction is viewed as the initial step of most cardiovascular diseases.Many studies have indicated that periodontal pathogens,especially Porphyromonas gingivalis,are closely correlated with vascular endothelial homeostasis,but the function of P.gingivalis and the underlying mechanisms are still elusive.To illuminate the effects and elucidate the mechanisms of P.gingivalis on endothelial structural integrity,we developed P.gingivalis infection models in vivo and in vitro.Endothelial cell proliferation,differentiation and apoptosis were detected.Here,we showed that P.gingivalis can impair endothelial integrity by inhibiting cell proliferation and inducing endothelial mesenchymal transformation and apoptosis of endothelial cells,which reduce the cell levels and cause the endothelium to lose its ability to repair itself.A mechanistic analysis showed that TLR antagonist or NF-κB signalling inhibitor can largely rescue the damaged integrity of the endothelium caused by P.gingivalis,suggesting that TLR-NF-κB signalling plays a vital role in vascular endothelial homeostasis destroyed by P.gingivalis.These results suggest a potential intervention method for the prevention and treatment of cardiovascular disease.
