Distinct modulation of microglial amyloid β phagocytosis and migration by neuropeptidesi

Microglial activation plays an integral role in the development and course of neurodegeneration. Although neuropeptides such as bradykinin (BK), somatostatin (SST), and endothelin (ET) are known to be important mediators of inflammation in the periphery, evidence of a similar function in brain is scarce. Using immunocytochemistry, we demonstrate the expression of receptors for BK (B1, B2 subtypes), ET (ETA, ETB subtypes) and SST (SST 2, 3, 4 subtypes) in primary microglia and microglial cell lines. Exposure of BV2 and N9, as well as primary microglial cells to BK or SST increased Aβ uptake in a concentration-dependent manner, whereas endothelin decreased Aβ uptake. This was caused by increased phagocytosis of Aβ since the rate of intracellular Aβ degradation remained unaffected. All neuropeptides increased chemotactic activity of microglia. In addition, BK reduced Aβ-induced expression of proinflammatory genes including iNOS and COX-2. ET decreased the Aβ-induced expression of monocyte chemoattractant protein 1 and interleukin-6. These results suggest that neuropeptides play an important role in chemotaxis and Aβ clearance and modulate the brain's response to neuroinflammatory processes

The Severity of Human Peri-Implantitis Lesions Correlates with the Level of Submucosal Microbial Dysbiosis

AIM To cross-sectionally analyse the submucosal microbiome of peri-implantitis (PI) lesions at different severity levels. MATERIALS AND METHODS Microbial signatures of 45 submucosal plaque samples from untreated PI lesions obtained from 30 non-smoking, systemically healthy subjects were assessed by 16s sequencing. Linear mixed models were used to identify taxa with differential abundance by probing depth, after correction for age, gender, and multiple samples per subject. Network analyses were performed to identify groups of taxa with mutual occurrence or exclusion. Subsequently, the effects of peri-implant probing depth on submucosal microbial dysbiosis were calculated using the microbial dysbiosis index. RESULTS In total, we identified 337 different taxa in the submucosal microbiome of PI. Total abundance of 12 taxa correlated significantly with increasing probing depth; a significant relationship with lower probing depth was found for 16 taxa. Network analysis identified two mutually exclusive complexes associated with shallow pockets and deeper pockets, respectively. Deeper peri-implant pockets were associated with significantly increased dysbiosis. CONCLUSION Increases in peri-implant pocket depth are associated with substantial changes in the submucosal microbiome and increasing levels of dysbiosis

Longitudinal co-site optical microscopy study on the chelating ability of etidronate and EDTA using a comparative single-tooth model

In the present study the smear layer dissolution kinetics of 18% etidronate (HEBP), 9% HEBP, and 17% ethylenediaminetetraacetic acid (EDTA) on human dentin were quantitatively and longitudinally analyzed by using a single-tooth comparative model. Coronal dentin disks were prepared from 3 maxillary human molars. A standardized smear layer was produced on the pulpal side of each disk. The smear layer-covered surface was divided into 3 similar areas. Each of these was then exposed to 1 of the 3 irrigants under investigation, whereas the others were covered with adhesive tape. Co-site image sequences of the areas under investigation were obtained after several cumulative demineralization times. Sixteen images were obtained from each dentin area of each tooth for each experimental time at 1000x magnification. An image processing and analysis sequence measured sets of images, providing data of area fraction for thousands of tubules over time and allowing us to quantitatively follow the effect of the chelating substances. The Kruskal-Wallis H test and Dunn multiple comparison test were used to analyze the data. Overall, it can be concluded that the demineralization kinetics promoted by both 9% HEBP and 18% HEBP were significantly slower than those of 17% EDTA (P < .05). In addition, the single-tooth model is advantageous over the first co-site optical microscopy dentin assessments when different chelator solutions are compared

European Journal of Clinical Investigation / GDF15 in solid vs nonsolid treatmentnaïve malignancies

Aim GDF15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF15 to other cardiac biomarkers and the general association of GDF15 on prognosis in an unselected cohort of treatmentnaïve cancer patients. Methods We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF15 concentrations were determined alongside other cardiac and routine laboratory markers. Allcause mortality was defined as primary endpoint. Results GDF15 levels were 338 ng/L (IQR:205534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF15 [435 ng/L (IQR:279614) vs 266 ng/L (IQR:175427), P < .001]. GDF15 correlated positively with inflammatory status reflected by CRP, SAA and IL6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NTproBNP, hsTnT, MRproADM and CTproET1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF15 was significantly associated with allcause mortality after multivariate adjustment [adj.HR for ln(GDF15) 1.78, 95%CI:1.472.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF15 with outcome in myelodysplastic and myeloproliferative disease. Conclusions Elevated plasma GDF15 is associated with progressing disease severity and poor prognosis in solid tumours of treatmentnaïve cancer patients. GDF15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF15 represents a promising target for our pathophysiologic understanding in cardiooncology linking conditions of both cardiac and neoplastic disease.(VLID)510161

Nitric Oxide Decreases the Enzymatic Activity of Insulin Degrading Enzyme in APP/PS1 Mice

peer reviewedNitric oxide has been implicated in the regulation of enzyme activity, particularly the activity of metalloproteinases. Since the inducible form of the nitric oxide synthase (NOS2), is upregulated in Alzheimer's disease, we investigated the activity of two amyloid β degrading enzymes, IDE and neprilysin. In vitro we demonstrated that the activity of IDE was inhibited by *NO donor Sin-1, whereas activity of neprilysin remained unaffected. In vivo the activity of insulin-degrading enzyme was lowered in APP/PS1 mice, but not in APP/PS1/NOS2(-/-) mice. These data suggest that NOS2 upregulation impairs amyloid β degradation through negative regulation of IDE activity and thus loss of NOS2 activity will positively influence amyloid β clearance