Odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to ...clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-β1) and Galectin-3. P.g.-secreted trypsin-like enzyme gingipain; an activator of protease-activated receptor 2 (PAR2) stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-β1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFβ-receptor II resulting in increasing sensitivity for TGF-β1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-β1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-β1 and Gal-3 production from HSCs and hepatocytes.
...the accessibility of the neck structures to fine needle aspirations and direct or computed tomographic-guided core biopsies allows for effective and initial pathologic assessment diagnostic tools ...11-15. ...the terms ameloblastic carcinoma and odontogenic sarcomas were retained, whereas all other descriptive terms including primary, differentiated, and malignant were omitted. Pathology and genetics of head and neck tumours, 3rd ed., 2005, IARC Press, Lyon 3 S. Fleskens, P. Slootweg, Grading systems in head and neck dysplasias: their prognostic value, weakness and utility, Head Neck Oncol, Vol. 1, 2009, 11 4 N Gale, R. Blagus, S.K. Mofty, Evaluation of new grading system for laryngeal squamous intraepithelial lesions-a proposed useful classification, Histopathology, Vol. 65, 2014, 456-464 5 A.J. Kimple, G.K. Austin, R.N. Shah, Polymorphous low grade adenocarcinoma: a case series and determination of recurrence laryngoscope, Vol. 124, 2014, 2714-2719 6 T.D. Patel, A. Vazquez, E. Marchiano, R.C. Park, S. Barendas, J.A. Eloy, Polymorphous low grade carcinoma of the head and neck: a population-based study of 460 cases, Laryngoscope, Vol. 125, 2016, 1644-1649 7 K.K. Ang, J. Harris, R. Wheeler, Human papillomavirus and survival of patients with oropharyngeal cancer, N Engl J Med, Vol. 363, 2010, 24-35 8 A.K. Chaturvedi, E.A. Engels, R.M. Pfeiffer, Human papillomavirus and rising oropharyngeal cancer incidence in the United States, J Clin Oncol, Vol. 29, 2011, 4294-4301 9 M.L. Gillison, Q. Zhang, R. Jordan, Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer, J Clin Oncol, Vol. 30, 2012, 2102-2111 10 M. Lechner, G.M. Frampton, T. Fenton, Genome Med, Vol. 5, 2013, 49 11 A Ferlito, G Bertino, A Rinaldo, G.M. Mannara, K.O. Deneng, A review of heterotopia and associated salivary glands neoplasms of the head and neck, J Laryngol Otol, Vol. 113, 1999, 299-303 13 J Golledge, H Ellis, The etiology of lateral cervical (branchial) cysts: past and present theories, J Laryngol Otol, Vol. 108, 1994, 653-659 14 J.K. La Plante, N.S. Person, G.L. Hedlund, Radiol Clin N Am, Vol. 53, 2015, 181-196 15 C. Garu, L.V. Johansen, J. Jacobsen, P. Gertsen, E. Andersen, B.B. Jensen, Cervical lymph node metastasis from unknown primary tumors. Suppl. 22, 2014, 6057 18 H. Haack, L.A. Johnson, C.J. Fry, Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody, Am J Surg Pathol, Vol. 33, 2009, 984-991 19 S.C. Huang, B.A. Ghossin, J.A. Bishop, Novel PAX3- NCOA1 fusion in biphenotypic sinonasal sarcoma with focal rhabdomyoblastic differentiation, Am J Surg Pathol, Vol. 40, 2016, 51-59 20 J.T. Lewis, A.M. Oliveria, A.G. Nascimento, Low-grade sino-nasal sarcoma with neural and myogenic features: a clinic-pathologic analysis of 28 cases, Am J Surg Pathol, Vol. 36, 2012, 517-525 21 J.S. Reis-Filho, R. Natrajan, R. Valcheva, Histopathology, Vol. 52, 2008, 840-846 22 A Kalova, T Vancek, R Sima, Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity, Am J Surg Pathol, Vol. 34, 2010, 599-608 23 T. Nagao, T.A. Gaffey, D.W. Vischer, Invasive micropapillary salivary duct carcinoma: a distinct histologic variant with biologic significance, Am J Surg Pathol, Vol. 28, 2004, 319-326 24 D Bell, M.E. Kupferman, M.D. Williams, A Rashid, A.K. El-Naggar, Primary colonic-type adenocarcinoma of the base of tongue: a previously unreported phenotype, Hum Pathol, Vol. 40, 2009, 1798-1802 25 A.M. Gillenwater, H. Fatani, A.K. El-Naggar, Primary intestinal-like adenocarcinoma of major salivary glands: 2 instances of previously undocumented phenotype, Head Neck, Vol. 35, 2013, E234-E236 26 R.H. Spiro, A.G. Huvas, E.W. Strong, Adenocarcinoma of salivary origin.
Cleft lip and palate is the most common congenital anomaly in the orofacial region. Autogenous iliac bone graft, in general, has been employed for closing the bone defect at the alveolar cleft. ...However, such iliac bone graft provides patients with substantial surgical and psychological invasions. Consequently, development of a less invasive method has been highly anticipated. Stem cells from human exfoliated deciduous teeth (SHED) are a major candidate for playing a significant role in tissue engineering and regenerative medicine. The aim of this study was to elucidate the nature of bone regeneration by SHED as compared to that of human dental pulp stem cells (hDPSCs) and bone marrow mesenchymal stem cells (hBMSCs). The stems cells derived from pulp tissues and bone marrow were transplanted with a polylactic-coglycolic acid barrier membrane as a scaffold, for use in bone regeneration in an artificial bone defect of 4 mm in diameter in the calvaria of immunodeficient mice. Three-dimensional analysis using micro CT and histological evaluation were performed. Degree of bone regeneration with SHED relative to the bone defect was almost equivalent to that with hDPSCs and hBMSCs 12 weeks after transplantation. The ratio of new bone formation relative to the pre-created bone defect was not significantly different among groups with SHED, hDPSCs and hBMSCs. In addition, as a result of histological evaluation, SHED produced the largest osteoid and widely distributed collagen fibers compared to hDPSCs and hBMSCs groups. Thus, SHED transplantation exerted bone regeneration ability sufficient for the repair of bone defect. The present study has demonstrated that SHED is one of the best candidate as a cell source for the reconstruction of alveolar cleft due to the bone regeneration ability with less surgical invasion.
•Isolated SHED and hDPSCs share features with MSCs.•Transplantation of SHED and hDPSCs induced bone formation.•SHED induced same amount of newly formed bone as hDPSCs and hBMSCs.•SHED is one of the best cell source candidates for reconstructing an alveolar cleft.
Background
We investigated the effects of dental infection with
Porphyromonas gingivalis
(
P.g.
), an important periodontal pathogen, on NASH progression, by feeding mice a high fat diet (HFD)and ...examining
P.g.
infection in the liver of NASH patients.
Methods
C57BL/6J mice were fed either chow-diet (CD) or HFD for 12 weeks, and then half of the mice in each group were infected with
P.g.
from the pulp chamber (HFD-
P.g.
(−), HFD-
P.g.
(+), CD-
P.g.
(−) and CD-
P.g.
(+)). Histological and immunohistochemical examinations, measurement of serum lipopolysaccharide (LPS) levels and ELISA for cytokines in the liver were performed. We then studied the effects of LPS from
P.g.
(
P.g.
-LPS) on palmitate-induced steatotic hepatocytes in vitro, and performed immunohistochemical detection of
P.g.
in liver biopsy specimens of NASH patients.
Results
Serum levels of LPS are upregulated in
P.g.
(+) groups. Steatosis of the liver developed in HFD groups, and foci of Mac2-positive macrophages were prominent in HFD-
P.g.
(+).
P.g.
was detected in Kupffer cells and hepatocytes. Interestingly, areas of fibrosis with proliferation of hepatic stellate cells and collagen formation were only observed in HFD-
P.g.
(+). In steatotic hepatocytes, expression of TLR2, one of the
P.g.
-LPS receptors, was upregulated.
P.g.
-LPS further increased mRNA levels of palmitate-induced inflammasome and proinflammatory cytokines in steatotic hepatocytes. We demonstrated for the first time that
P.g.
existed in the liver of NASH patients with advanced fibrosis.
Conclusions
Dental infection of
P.g.
may play an important role in NASH progression through upregulation of the
P.g.
-LPS-TLR2 pathway and activation of inflammasomes. Therefore, preventing and/or eliminating
P.g.
infection by dental therapy may have a beneficial impact on management of NASH.
Dynamic probabilistic risk assessment (PRA), which handles epistemic and aleatory uncertainties by coupling the thermal-hydraulics simulation and probabilistic sampling, enables a more realistic and ...detailed analysis than conventional PRA. However, enormous calculation costs are incurred by these improvements. One solution is to select an appropriate sampling method. In this paper, we applied the Monte Carlo, Latin hypercube, grid-point, and quasi-Monte Carlo sampling methods to the dynamic PRA of a station blackout sequence in a boiling water reactor and compared each method. The result indicated that quasi-Monte Carlo sampling method handles the uncertainties most effectively in the assumed scenario.
Cellular senescence acts as a barrier to cancer progression, and microRNAs (miRNAs) are thought to be potential senescence regulators. However, whether senescence-associated miRNAs (SA-miRNAs) ...contribute to tumor suppression remains unknown. Here, we report that miR-22, a novel SA-miRNA, has an impact on tumorigenesis. miR-22 is up-regulated in human senescent fibroblasts and epithelial cells but down-regulated in various cancer cell lines. miR-22 overexpression induces growth suppression and acquisition of a senescent phenotype in human normal and cancer cells. miR-22 knockdown in presenescent fibroblasts decreased cell size, and cells became more compact. miR-22-induced senescence also decreases cell motility and inhibits cell invasion in vitro. Synthetic miR-22 delivery suppresses tumor growth and metastasis in vivo by inducing cellular senescence in a mouse model of breast carcinoma. We confirmed that CDK6, SIRT1, and Sp1, genes involved in the senescence program, are direct targets of miR-22. Our study provides the first evidence that miR-22 restores the cellular senescence program in cancer cells and acts as a tumor suppressor.
Epidemiological studies have revealed a link between dental infection and preterm birth or low birth weight (PTB/LBW), however, the underlying mechanisms remain unclear. Progress in understanding the ...associated mechanisms has been limited in part by lack of an animal model for chronic infection-induced PTB/LBW, mimicking pregnancy under conditions of periodontitis. We aimed to establish a mouse model of chronic periodontitis in order to investigate the link between periodontitis and PTB/LBW.
To establish chronic inflammation beginning with dental infection, we surgically opened mouse (female, 8 weeks old) 1st molar pulp chambers and directly infected with w83 strain Porphyromonas gingivalis (P.g.), a keystone periodontal pathogen. Mating was initiated at 6 wks post-infection, by which time dental granuloma tissue had developed and live P.g. was cultured from extracted tooth root, which serves as a persistent source of P.g. The gestational day (gd) and birth weight were recorded during for P.g.-infected and control mice, and serum and placental tissues were collected at gd 15 to evaluate the systemic and local conditions during pregnancy.
Dental infection with P.g. significantly increased circulating TNF-α (2.5-fold), IL-17 (2-fold), IL-6 (2-fold) and IL-1β (2-fold). The P.g.-infected group delivered at gd 18.25 vs. gd 20.45 in the non-infected control (NC) group (p < 0.01), and pups exhibited LBW compared to controls (p < 0.01). P.g. was localized to placental tissues by immunohistochemistry and PCR, and defects in placental tissues of P.g. infected mice included premature rupture of membrane, placental detachment, degenerative changes in trophoblasts and endothelial cells, including necrotic areas. P.g. infection caused significantly increased numbers of polymorphonuclear leukocytes (PMNLs) and macrophages in placental tissues, associated with increased local expression of pro-inflammatory mediators including TNF-α and COX-2. Further placental tissue damage was indicated in P.g. infected mice by decreased CD-31 in endothelial cells, increased expression of 8OHdG, an indicator of oxidative DNA damage, and cleaved caspase-3, a marker of apoptosis. In vitro, P.g. lipopolysaccharide significantly increased expression of COX-2, IL-8 and TNF-α, in HTR-8 trophoblasts in an NF-κB-dependent fashion.
Our novel mouse model supports previous epidemiological studies signifying dental infection as predisposing factor for PTB/LBW. We demonstrate PTB and LBW in infected mice, translocation of P.g to placental tissues, increased circulating and local pro-inflammatory markers, and the capability of P.g. LPS to directly induce cytokine production in trophoblasts, in vitro. These findings further underscore the importance of local and systemic infections and inflammation during pregnancy and suggest that prevention and/or elimination of dental infections such as marginal or periapical periodontitis before pregnancy may have a beneficial effect on PTB/LBW.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Primordial odontogenic tumor (POT) is a rare lesion in the jaw which has been included as a new entity of benign mixed epithelial and mesenchymal odontogenic tumour in the latest World Health ...Organization (WHO) classification (2017). Only seven cases have been reported. It typically occurs in the posterior mandible. We report an additional case of POT in the maxilla of an 8‐year‐old girl presenting with an asymptomatic buccal enlargement. A well‐defined, unilocular, radiolucent lesion was observed radiographically. Histologically, the tumor was mostly composed of loose fibrous connective tissue resembling dental papilla and a single layer of columnar epithelium covering the periphery of the tumor. In part, cords or nests of epithelium were present in the mesenchyme close to the periphery. Nestin, a marker of odontogenic ectomesenchyme, was positive in the mesenchymal tumor cells. We finally diagnosed the lesion as POT considering the possibility of other odontogenic tumors like ameloblastic fibroma or developing odontoma as a differential diagnosis. The patient shows no recurrence after 16 months. This case is the first report from Japan using this novel diagnosis POT after it was recognized and defined in the latest WHO classification.
Background and aims
The risk factors in the progression of nonalcoholic fatty liver disease (NAFLD) have not been fully clarified.
Porphyromonas gingivalis
(
P.g
) has been considered to be a ...confounding risk factor for systemic diseases. We aimed to evaluate the effect of
P.g
infection on risk of progression to NASH.
Methods
(1) Serum IgG antibody titers against
P.g
fimbriae (fimA) in 200 biopsy-proven NAFLD patients were measured by ELISA and compared with histological findings. (2) C57BL/6J mice were fed a control diet (CD) or high-fat diet (HFD) with or without
P.g
-odontogenic infection and analyzed histologically. Mouse livers were analyzed using CE–TOFMS and LC–TOFMS.
Results
(1) A significant correlation between fibrosis progression and antibody titers against
P.g
possessing fimA type 4 was identified (
P
= 0.0081). Multivariate analysis identified older age and type 4
P.g
-positivity as risk factors for advanced fibrosis. (2) Fibrosis and steatosis were more severe in HFD
P.g
(+) mice compared with HFD
P.g
(−) mice. In metabolome analysis, fatty acid metabolism was significantly disrupted with HFD in
P.g
-infected mouse livers. Monounsaturated/saturated fatty acid ratios were significantly higher in the HFD
P.g
(+) group than in the HFD
P.g
(−) group (
P
< 0.05). Moreover, expression levels of
SCD1
and
ELOVL6
were significantly reduced.
Conclusions
These results suggest that
P.g
infection is an important risk factor for pathological progression in NAFLD. Increase in the monounsaturated/saturated fatty acid ratio may be an important change that facilitates progression of NAFLD.
Porphyromonas gingivalis (P.g.), a major periodontal pathogen is a known risk factor for various systemic diseases. However, the relationship between P.g. and nonalcoholic steatohepatitis ...(NASH)-related hepatocellular carcinoma (HCC) is unclear. Thus, we aimed to elucidate whether P.g.-odontogenic infection promotes NASH-related HCC development/progression and to clarify its mechanism. Using high-fat diet (HFD)-induced NASH mouse model, P.g. was infected odontogenically. After 60 weeks of infection, tumor profiles were examined. Chow diet (CD) groups were also prepared at 60 weeks. Nodule formation was only seen in HFD-mice. P.g.-odontogenic infection significantly increased the mean nodule area (P = 0.0188) and tended to promote histological progression score after 60 weeks (P = 0.0956). Interestingly, P.g. was detected in the liver. HFD-P.g. (+) showed numerous TNF-α positive hepatic crown-like structures and 8-OHdG expression in the non-neoplastic liver. In P.g.-infected hepatocytes, phosphorylation of integrin β1 signaling molecules (FAK/ERK/AKT) was upregulated in vitro. In fact, total AKT in the liver of HFD-P.g. (+) was higher than that of HFD-P.g. (-). P.g.-infected hepatocytes showed increased cell proliferation and migration, and decreased doxorubicin-mediated apoptosis. Integrin β1 knockdown inhibited these phenotypic changes. P.g.-odontogenic infection may promote the progression of neoplastic nodule formation in an HFD-induced NASH mouse model via integrin signaling and TNF-α induced oxidative DNA damage.
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