It is well known that dental pulp tissue can evoke some of the most severe acute inflammation observed in the human body. We found that dental pulp cells secrete a factor that induces tumor necrosis ...factor-α production from macrophages, and designated this factor, dental pulp cell-derived powerful inducer of TNF-α (DPIT). DPIT was induced in dental pulp cells and transported to recipient cells via microvesicles. Treatment of dental pulp cells with a PKR inhibitor markedly suppressed DPIT activity, and weak interferon signals were constitutively activated inside the cells. In recipient macrophages, stimulation with DPIT-containing supernatants from pulp cells resulted in activation of both nuclear factor-κB and MAP kinases like JNK and p38. Proteomics analyses revealed that many stress granule-related proteins were present in supernatants from dental pulp cells as well as microvesicle marker proteins like GAPDH, β-actin, HSPA8, HSPB1, HSPE1, and HSPD1. Furthermore, giant molecule AHNAK and PKR were detected in microvesicles derived from dental pulp cells, and gene silencing of AHNAK in dental pulp cells led to reduced DPIT activity. Thus, it appeared that the core protein of DPIT was PKR, and that PKR was maintained in an active state in stress granule aggregates with AHNAK and transported via microvesicles. The activity of DPIT for TNF-α induction was far superior to that of gram-negative bacterial endotoxin. Therefore, we, report for the first time, that active PKR is transported via microvesicles as stress granule aggregates and induces powerful inflammatory signals in macrophages.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
Several chemokines play important roles in recruiting the monocyte/macrophage lineage into adipose tissues. We previously found CCL19 was highly expressed in adipocytes cocultured with ...macrophages stimulated by endotoxin. This study aimed to evaluate the role of CCL19‐CCR7 axis on obesity and insulin resistance.
Methods
Serum CCL19 concentration was examined in obese model mice challenged by endotoxin. CCL19 receptor‐null, Ccr7−/−, mice and wild‐type mice fed a high‐fat diet or normal diet were used to investigate the role of CCL19 signals on obesity‐associated inflammation.
Results
CCL19 protein was elevated in the sera of obese model mice challenged by endotoxin. Ccr7−/− mice were protected from diet‐induced obesity and insulin resistance. The adipose tissue and liver expression of inflammatory genes of Ccr7−/− mice was much lower than in diet‐induced obese mice. Ccr7−/− mice were protected from fatty liver and dyslipidemia and exhibited increased thermogenesis on high‐fat feeding. CCL19 attracts activated dendritic cells (DC). The expression of the DC markers, CD11b and 11c, was not observed in the adipose tissues of Ccr7−/− mice fed a high‐fat diet, which might be closely associated with the protection of these mice from obesity.
Conclusions
The CCL19‐CCR7 pathway associates with the development of high‐fat–induced obesity and insulin resistance.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Chronic kidney disease (CKD) is an important risk factor for coronary heart disease, and previous studies indicated the involvement of low-grade inflammation in the pathogenesis of CKD.
The study was ...designed to (i) identify and confirm genes and their products upregulated in mesangial cells cocultured with endotoxin-stimulated macrophages and (ii) determine the clinical relevance of genes and proteins upregulated in mesangial cells under inflammatory conditions by an epidemiological approach.
DNA microarray analysis revealed upregulated expression of many genes and their products including several cytokines and chemokines, as well as the inflammatory marker, lipocalin 2 gene. The gene expression and protein upregulation of lipocalin 2 were synergistically affected by endotoxin and tumor necrosis factor (TNF)-α stimulation. In human studies, lipocalin 2 level was significantly associated with creatinine (r = 0.419, P < 0.001) and negatively associated with eGFR (r = -0.365, P < 0.001). Multiple logistic regression analysis revealed a significant association between lipocalin 2 and soluble tumor necrosis factor receptor 2 (sTNF-R2), eGFR and uric acid in general subjects attending regular annual medical check-up (n = 420). When subjects with diabetes were excluded from the analysis, lipocalin 2 remained associated with sTNF-R2, eGFR and uric acid.
Since an activated TNF system, as demonstrated by elevated sTNF-R2, and elevated uric acid were recently implicated in an elevated CKD risk, we conclude that inflammation could play an important role in the pathogenesis of CKD, and that lipocalin 2 is a potential universal marker for impaired kidney function. Furthermore, the results obtained by the current microarray analysis could improve the understanding of gene profiles associated with the pathophysiology of CKD under inflammatory conditions.
The effect of smoking on leptin regulation is controversial. Smoking may induce low-grade inflammation. Recent series of studies indicated the critical role of macrophage migration in the ...establishment of adipose tissue inflammation. In this study, we aimed to see the effects of smoking and inflammation on leptin regulation both at cellular and epidemiological levels.
We compared the concentration of inflammatory markers and serum leptin levels among Japanese male subjects. Additionally, leptin and intercellular adhesion molecule (ICAM) -1 gene expression was assessed in adipocytes co-cultured with or without macrophages in the presence or absence of nicotine and/or lipopolysaccharide (LPS).
In subjects with BMI below 25 kg/m2, both WBC counts and soluble-ICAM-1 levels are significantly higher in smokers than in non-smokers. However, leptin concentration did not differ according to smoking status. However, in subjects with BMI over 25 kg/m2, smokers exhibited significantly lower serum leptin level as well as higher WBC counts and s-ICAM-1 concentration as compared with non-smokers. Leptin gene expression was markedly suppressed in adipocytes co-cultured with macrophages than in adipocyte culture alone. Furthermore, nicotine further suppressed leptin gene expression. ICAM-1 gene expression was markedly up-regulated in adipocytes co-cultured with macrophages when stimulated with LPS.
Adipose tissue inflammation appears to down-regulate leptin expression in adipose tissues. Nicotine further suppresses leptin expression. Thus, both smoking and inflammation may diminish leptin effect in obese subjects. Therefore, obese, but not normal weight, smokers might be more resistant to weight loss than non-smokers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Chronic low-grade infection has been suggested to be associated with metabolic disorder such as diabetes. However, the molecular mechanism underlying this important association is largely unknown. ...The only clue established so far is that many subjects exhibit elevated levels of C-reactive protein as measured by highly sensitive assay. Here, we hypothesized that adipocyte–macrophage interaction plays a key role in amplifying such low grade infection to the level of influencing metabolic disorders. The presence of macrophages in abdominal adipose tissues was investigated by immunohistochemistry. To see whether molecules associated with acute phase protein, LPS signaling, and persistent recruitment of monocytes, are produced at higher amounts in adipocytes co-cultured with macrophages stimulated with low concentration of LPS (1 ng/ml), we measured serum amyloid A (SAA), LPS binding protein (LBP), soluble CD14 (sCD14), and RANTES levels in culture supernatant of co-cultures. Lastly, we investigated in vivo effect of low-grade LPS infusion on the production of these molecules using obese model mice. The macrophages were certainly identified in abdominal adipose tissues. Investigated molecules, especially LBP, SAA, and RANTES were produced at higher amounts in co-cultures stimulated with LPS compared with the cells without LPS. The ob/ob, and high-fat diet-induced obesity mice produced higher amounts of LBP, SAA, and RANTES one day after LPS infusion (1 ng/ml/g body weight) compared with ob/– and normal-fat fed control mice. Thus, adipocytes and infiltrated macrophages, and their interaction with low endotoxin stimulation appear to play an important role in amplifying and maintaining LPS-induced low-grade inflammation.
Purpose: Matrix trioxide aggregate (MTA) has been used for direct pulp-capping as well as perforation repair due to its potent ability to induce hard tissue regeneration. Pulp exposure, usually ...caused by tooth fracture and carious tooth treatment, involves the physical damage of pulp extracellular matrix. Therefore, when cells invade the damaged space from surrounding tissue, the existence of an adhesive substrate to aid cell proliferation and differentiation of invading cells is the key factor influencing the prognosis of pulp-capping treatment. In this study, we examined the effects of MTA on the adhesion, proliferation and apoptosis of human dental pulp cells (hDPCs) by comparison with composite resin (CR) and glass ionomer cement (GIC). Materials and methods: Ninety-six-well plates were coated with MTA, CR, GIC and fibronectin. Cells were suspended in serum-free medium and then seeded onto coated wells. After 1.5-hr incubation at 37°C, the wells were rinsed to remove non-adherent cells. The number of adherent cells was quantified using the Cell Titer Glo Luminescent Cell Viability Assay Kit. For proliferation assay, these cells were seeded onto MTA, CR and GIC and attached cells were quantified. After 1.5-hr incubation, serum-free medium was replaced with 10% serum medium and cells were cultured onto these substrates for 72 hrs. The ability to induce apoptosis was evaluated by caspase 3/7 activity. Result: MTA facilitated the adhesion of hDPCs, while CR and GIC did not. However, the adhesive effect of MTA was much weaker than that of fibronectin. hDPCs could attach onto MTA but not CR or GIC, even 72 hrs after seeding, although the number of attached cells gradually decreased during the culture period. These observations suggest that MTA could be used as a substrate for the adhesion, but not a scaffold for the proliferation, of hDPCs. A drastic increase of caspase 3/7 activity was observed when hDPCs were cultured onto CR and GIC. In contrast, MTA did not induce it. Conclusions: Compared with CR and GIC, MTA is a good substrate for hDPC adhesion. These differential adhesive effects may be explained by the differential abilities for inducing pro-apoptotic signals in hDPCs. However, the effect of MTA as a cell adhesion substrate was much weaker than that of fibronectin. More importantly, MTA was unable to induce the proliferation of hDPCs on it. Thus, the co-addition of MTA with other adhesive and migratory proteins such as fibronectin may induce better wound healing and pulp tissue regeneration in vivo.
Cocaine-associated environmental cues elicit craving and relapse to cocaine use by recalling the rewarding memory of cocaine. However, the neuronal mechanisms underlying the expression of ...cocaine-associated memory are not fully understood. Here, we investigated the possible contribution of γ-aminobutyrate (GABA)ergic neurons in the nucleus accumbens (NAc), a key brain region associated with the rewarding and reinforcing effects of cocaine, to the expression of cocaine-associated memory using the conditioned place preference (CPP) paradigm combined with designer receptors exclusively activated by designer drugs (DREADD) technology. The inhibitory DREADD hM4Di was selectively expressed in NAc GABAergic neurons of vesicular GABA transporter-Cre (vGAT-Cre) mice by infusing adeno-associated virus (AAV) vectors. Ex vivo electrophysiological recordings revealed that bath application of clozapine-N-oxide (CNO) significantly hyperpolarized membrane potentials and reduced the number of spikes induced by depolarizing current injections in hM4Di-positive NAc neurons. Additionally, systemic CNO injections into cocaine-conditioned mice 30 min before posttest session significantly reduced CPP scores compared to saline-injected mice. These results indicate that chemogenetic inhibition of NAc GABAergic neurons attenuated the expression of cocaine CPP, suggesting that NAc GABAergic neuronal activation is required for the environmental context-induced expression of cocaine-associated memory.
Purpose
The number of laparoscopic surgeries for colorectal cancer (CRC) in elderly patients has been increasing. We examined the short- and mid-term outcomes of laparoscopic surgery for CRC in ...oldest-old patients (≥ 85 years old) compared with the outcomes in younger patients (< 85 years old).
Methods
We retrospectively reviewed primary tumor resection for CRC from April 2015 to December 2020 at six hospitals. Short- and mid-term outcomes were compared after propensity score matching.
Results
From the 1374 patients, 126 matched pairs were selected. In the matched cohort, the duration of postoperative hospital stay was longer in the oldest-old patients than in the younger patients (15 days vs. 12 days,
p
= 0.001). There were no significant differences between the groups in the rate of Clavien–Dindo grade ≥ 2 postoperative complications (21.4% vs. 15.1%,
p
= 0.254). The oldest-old patients showed a poorer overall survival (OS) than the younger patients (3-year OS, 79.9% vs. 93.5%,
p
= 0.005) but comparable recurrence-free survival (RFS) (3-year RFS, 72.2% vs. 81.6%,
p
= 0.530) and cancer-specific survival rates (CSS) (3-year CSS, 90.1% vs. 99.0%,
p
= 0.124).
Conclusion
Laparoscopic surgery for CRC in oldest-old patients was performed safely with comparable short-term outcomes to those in younger patients. Although the OS was poorer in the oldest-old patients than in the younger patients, the oncological mid-term outcomes were comparable. Laparoscopic surgery for CRC can be considered acceptable as a treatment in oldest-old patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
The effectiveness of primary tumor resection (PTR) for asymptomatic stage IV colorectal cancer patients to continue prolonged and safe systemic chemotherapy has recently been re-evaluated. ...However, postoperative complications lead to a prolonged hospital stay and delay systemic treatment, which could result in a poor oncologic outcome. The objective of this study was to identify the risk factors for morbidity and delay of systemic chemotherapy in such patients.
Methods
Between April 2016 and March 2018, 115 consecutive colorectal cancer patients with distant metastasis who had no clinical symptoms and underwent PTR in all participating hospitals were retrospectively reviewed. The patients were divided into two groups according to the presence (CD ≥ 2,
n
= 23) or absence (CD < 2,
n
= 92) of postoperative complications.
Results
The proportion of combined resection of adjacent organs was significantly higher in the postoperative complication group (
p
= 0.014). Complications were significantly correlated with longer hospital stay (
p
< 0.001) and delay of first postoperative treatment (
p
= 0.005). Univariate and multivariate analyses showed that combined resection (odds ratio 4.593,
p
= 0.010) was the independent predictor for postoperative complications. Median survival time was 8.5 months. Postoperative complications were not associated with overall survival, but four patients (3.5%) could not receive systemic chemotherapy because of prolonged postoperative complications.
Conclusions
Although PTR for asymptomatic stage IV CRC patients showed an acceptable prognosis, appropriate patient selection is needed to obtain its true benefit.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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