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.
Atrial fibrillation (AF) is associated with a fivefold risk of stroke and thrombotic embolism, which are usually derived from the left atrial appendage (LAA). Spontaneous echo contrast (SEC) is known ...as a risk factor for thrombosis.
Porphyromonas gingivalis
(
P.
gingivalis
) has some prothrombotic effects and plays a key role in periodontitis and oral-systemic disease connection. We aimed to clarify the relationship between
P. gingivalis
and LAA SEC among AF patients. A total of 569 AF ablation candidates were enrolled in the present study. LAA SEC was categorized into nondense SEC and dense SEC based on transesophageal echocardiography. Serum immunoglobulin G antibody titers of
P. gingivalis
fimA subtypes (types I–IV) were measured with an enzyme-linked immunosorbent assay. The levels of antibody titers were categorized into high (> mean + 3 standard deviation) and low values. A total of 513 (90%) patients were included in the nondense SEC group, and 56 (10%) were included in the dense SEC group. Multivariate regression analysis revealed that the high-value serum antibody titers of
P. gingivalis
types II and IV were independently associated with dense SEC type II: adjusted odds ratio (OR) 2.220; 95% confidence interval (CI) 1.062–4.643;
P
= 0.02; and type IV: adjusted OR 3.169; 95% CI 1.058–6.657;
P
= 0.002. The results revealed that
P. gingivalis
types II and IV are related to LAA SEC severity among AF patients who receive appropriate anticoagulation therapy.
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
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.
Introduction
Inflammation is one of the main causes of atrial fibrillation (AF) recurrence after ablation. Porphyromonas gingivalis is a key periodontal pathogen in the oral–systemic disease ...connection and serum immunoglobulin G (IgG) antibody titers against P. gingivalis reflect the clinical status of periodontitis. This study aimed to investigate the relationship between late recurrence of AF after radiofrequency catheter ablation (RFCA) and serum IgG antibody titers against P. gingivalis.
Methods
A total of 596 AF patients (mean age, 64.9 ± 10.0 years; 69% male; 61% paroxysmal AF) who underwent a first session of RFCA were enrolled. Patients were carefully examined for late recurrence during a mean follow‐up period of 17.1 ± 14.5 months. Serum IgG antibody titers against P. gingivalis (types I–IV) were measured using enzyme‐linked immunosorbent assay. The results of serum antibody titers were divided into a high‐value and a low‐value group.
Results
Among the five P. gingivalis subtypes, serum antibody titer against P. gingivalis type IV was associated with late recurrence (odds ratio, 1.937; 95% confidence interval CI, 1.301–2.884; p = .002). Multivariate Cox proportional‐hazards regression analysis revealed that high‐value serum antibody titer against P. gingivalis type IV independently predicted late recurrence (paroxysmal AF: adjusted hazard ratio HR, 1.569; 95% CI, 1.010–2.427; p = .04; non‐paroxysmal AF: adjusted HR, 1.909; 95% CI, 1.213–3.005; p = .004).
Conclusion
Periodontitis was related to the late recurrence of AF after RFCA. P. gingivalis type IV may be pathogenic for AF recurrence after RFCA.
Non‐sebaceous lymphadenoma is a rare benign salivary gland tumor comprised of non‐sebaceous epithelial cells and lymphoid tissue. Although its clinicopathological features have been described, its ...histogenesis and genetic background have not yet been elucidated. MAML2 rearrangement and the resultant CRTC1/3‐MAML2 fusion gene are well‐known specific genetic changes in mucoepidermoid carcinoma. Here, we present a case of lymphoepithelial tumor characterized by histomorphology of the non‐sebaceous lymphadenoma and CRTC1‐MAML2 fusion gene. The patient was an 83‐year‐old woman with an 8‐year history of a solid, well‐circumscribed tumor in the parotid gland. Histologically, the tumor was surrounded by thin fibrous connective tissue and was composed of tubular‐cystic and solid nests of epithelial cells equally distributed in the lymphoid tissue. The histological features were suggestive of non‐sebaceous lymphadenoma. Although the histomorphology was not consistent with mucoepidermoid carcinoma, a diagnosis of non‐sebaceous lymphadenoma‐like mucoepidermoid carcinoma was made based on the presence of the CRTC1‐MAML2 fusion gene. The histological features alone could not establish the diagnosis, and ancillary molecular analysis was required.
Introduction
Although recent echocardiographic studies have suggested that left atrial appendage (LAA) remodeling contributes to the development of LAA thrombus (LAAT), histological evidence is ...absent. The objective of this study was to examine clinical parameters and histological findings to clarify the factors involved in LAAT formation.
Methods
A total of 64 patients (no atrial fibrillation AF, N = 22; paroxysmal AF, N = 16; nonparoxysmal AF, N = 26) who underwent LAA excision during surgery were enrolled. Transthoracic and transesophageal echocardiography were performed before surgery. We evaluated the fibrosis burden (%) in the excised LAA sections with Azan–Mallory staining in patients with a LAAT compared with those without.
Results
Patients with paroxysmal and non‐paroxysmal AF had a higher LAA fibrosis burden than those without AF (p = .005 and p < .0001, respectively). Among the patients enrolled, 16 had a LAAT and 15 of them had nonparoxysmal AF. Among the nonparoxysmal AF patients, those with a LAAT had significantly higher LAA fibrosis burden than those without (23.8% 14.8%–40.3% vs. 12.8% 7.4%–18.2%, p = .004) and echocardiographic parameters of the left atrial volume index (R = 0.543, p = .01), LAA depth (R = 0.452, p = .02), and LAA flow velocity (R = − 0.487, p = .01) were correlated with the LAA fibrosis burden.
Conclusion
This study provided histological evidence that LAA fibrosis is related to LAAT formation. Echocardiographic parameters of LAA remodeling and function were correlated with the LAA fibrosis burden.
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.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory bone destruction in which tumor necrosis factor alpha (TNF-α) plays a key role. Bovine lactoferrin (bLF) is a ...multifunctional protein with anti-inflammatory and immunomodulatory properties. This study aimed to clarify the inhibitory effects of bLF on the pathological progression of RA. The mannan-induced arthritis model in SKG mice (genetic RA model) was used. Orally applied liposomal bLF (LbLF) markedly reduced ankle joint swelling and bone destruction. Histologically, pannus formation and osteoclastic bone destruction were prevented in the LbLF-treated animals. Moreover, orally administered LbLF improved the balance between Th17 cells and regulatory T cells isolated from the spleen of mannan-treated SKG mice. In an in vitro study, the anti-inflammatory effects of bLF on TNF-α-induced TNF-α production and downstream signaling pathways were analyzed in human synovial fibroblasts from RA patients (RASFs). bLF suppressed TNF-α production from RASFs by inhibiting the nuclear factor kappa B and mitogen-activated protein kinase pathways. The intracellular accumulation of bLF in RASFs increased in an applied bLF dose-dependent manner. Knockdown of the lipoprotein receptor-related protein-1 (LRP1) siRNA gene reduced bLF expression in RASFs, indicating that exogenously applied bLF was mainly internalized through LRP-1. Immunoprecipitated proteins with anti-TNF receptor-associated factor 2 (TRAF2; an adapter protein/ubiquitin ligase) included bLF, indicating that bLF binds directly to the TRAF2-TRADD-RIP complex. This indicates that LbLF may effectively prevent the pathological progression of RA by suppressing TNF-α production by binding to the TRAF2-TRADD-RIP complex from the RASFs in the pannus. Therefore, supplemental administration of LbLF may have a beneficial effect on preventive/therapeutic reagents for RA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular ...carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells.
Methods
LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors.
Results
DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFβ. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC.
Conclusion
Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFβ.
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