Antioxidant enzymes in periodontitis

Publication date: Available online 25 August 2016
Source:Journal of Oral Biology and Craniofacial Research
Author(s): Shilpa Trivedi, Nand Lal
Periodontitis is basically an inflammatory disease initiated by the subgingival biofilm and modified by the individual's aberrant inflammatory/immune response. Various studies have pointed toward the role of oxidative stress in periodontitis. As the reactive oxygen species and antioxidants are in dynamic equilibrium, any disturbance in one would lead to changes in the other. As studying, individual antioxidants is a vast field, this review focuses on the role of antioxidant enzymes in periodontitis and in other related systemic conditions. It is highlighted that oxidative stress may be the missing link in these associations of periodontitis and other conditions. Also, the antioxidant enzymes may be considered a useful biomarker for periodontal diseases and antioxidant supplementation may be of help to reduce the burden of periodontal destruction without having much extra effort.



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Representativeness of the participants in the smoking Cessation in Pregnancy Incentives Trial (CPIT): a cross-sectional study

The limited representativeness of trial samples may restrict external validity. The aim of this study was to ascertain the representativeness of the population enrolled in the Cessation in Pregnancy Incentives...

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Walking adaptability therapy after stroke: study protocol for a randomized controlled trial

Walking in everyday life requires the ability to adapt walking to the environment. This adaptability is often impaired after stroke, and this might contribute to the increased fall risk after stroke. To improv...

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Ultradian rhythms in mammalian physiology and behavior

Publication date: October 2016
Source:Current Opinion in Neurobiology, Volume 40
Author(s): Brian J Prendergast, Irving Zucker
Diverse mammalian ultradian rhythms (URs) with periods in the 1–6h range, are omnipresent at multiple levels of biological organization and of functional and adaptive significance. Specification of neuroendocrine substrates that generate URs remains elusive. The suprachiasmatic (SCN) and arcuate (ARC) nuclei of the rodent hypothalamus subserve several behavioral URs. Recently, in a major advance, dopaminergic signaling in striatal circuitry, likely at D2 receptors, has been implicated in behavioral and thermoregulatory URs of mice. We propose a neural network in which reciprocal communication among the SCN, the ARC and striatal dopaminergic circuitry modulates the period and waveform of behavioral and physiological URs.



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Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo

Background

Although the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has become a prime target for antiangiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial.

Methods

Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineated autocrine signaling in glioma cell lines. The in vivo effects of VEGFR1 and VEGFR2 depletion were evaluated in orthotopic glioma xenograft models.

Results

VEGFR1 and VEGFR2 modulated glioma cell clonogenicity, viability, and invasiveness in vitro in an autocrine, cell–line-specific manner. VEGFR1 silencing promoted mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, whereas VEGFR2 silencing resulted in cell-type dependent activation of the protein kinase B (PKB)/AKT and MAPK/ERK pathways. These responses may represent specific escape mechanisms from VEGFR inhibition. The survival of orthotopic glioma-bearing mice was prolonged upon VEGFR1 silencing in the LNT-229, LN-308, and U87MG models and upon VEGFR2 silencing in LN-308 and U87MG. Disruption of VEGFR1 and VEGFR2 signaling was associated with decreased tumor size, increased tumor necrosis, or loss of matrix metalloproteinase 9 (MMP9) immunoreactivity. Neutralizing VEGF and PlGF by specific antibodies was superior to either antibody treatment alone in the VEGFR1-dependent LNT-229 model.

Conclusions

Differential dependence on autocrine signaling through VEGFR1 and VEGFR2 suggests a need for biomarker–stratified VEGF(R)-based therapeutic approaches to glioblastoma.

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Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function

Background

Gliomas are primary brain tumors that are associated with a poor prognosis. The introduction of new treatment modalities (including immunotherapy) for these neoplasms in the last 3 decades has resulted in only limited improvement in survival. Gliomas are known to create an immunosuppressive microenvironment that hampers the efficacy of (immuno)therapy. One component of this immunosuppressive environment is the myeloid-derived suppressor cell (MDSC).

Methods

We set out to analyze the presence and activation state of MDSCs in blood (n = 41) and tumor (n = 20) of glioma patients by measuring S100A8/9 and arginase using flow cytometry and qPCR. Inhibition of T cell proliferation and cytokine production after stimulation with anti-CD3/anti-CD28 coated beads was used to measure in vitro MDSC suppression capacity.

Results

We report a trend toward a tumor grade-dependent increase of both monocytic (M-) and polymorphonuclear (PMN-) MDSC subpopulations in the blood of patients with glioma. M-MDSCs of glioma patients have increased levels of intracellular S100A8/9 compared with M-MDSCs in healthy controls (HCs). Glioma patients also have increased S100A8/9 serum levels, which correlates with increased arginase activity in serum. PMN-MDSCs in both blood and tumor tissue demonstrated high expression of arginase. Furthermore, we assessed blood-derived PMN-MDSC function and showed that these cells have potent T cell suppressive function in vitro.

Conclusions

These data indicate a tumor grade-dependent increase of MDSCs in the blood of patients with a glioma. These MDSCs exhibit an increased activation state compared with MDSCs in HCs, independent of tumor grade.

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AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma

Background

Few prospective studies have assessed the role of bevacizumab and included a control arm with standard treatments for recurrent glioblastoma. We conducted a noncomparative phase II trial (AVAREG) to examine the efficacy of bevacizumab or fotemustine in this setting.

Methods

Eligible patients were randomized 2:1 to receive bevacizumab (10 mg/kg every 2 weeks) or fotemustine (75 mg/m² on days 1, 8, and 15, then 100 mg/m² every 3 weeks after a 35-day interval). The primary endpoint was 6-month overall survival (OS) rate (OS-6). No formal efficacy comparison was made between the treatment arms.

Results

Ninety-one patients were enrolled (bevacizumab n = 59; fotemustine n = 32). Median age was 57 years (range, 28–78 y), and patients had Eastern Cooperative Oncology Group performance status of 0 (n = 42), 1 (n = 35), or 2 (n = 14). OS-6 rate was 62.1% (95% confidence interval [CI], 48.4–74.5) with bevacizumab and 73.3% (95% CI, 54.1–87.7) with fotemustine. OS-6 rates were lower in bevacizumab-treated patients with MGMT promoter methylated tumors than in those with unmethylated tumors (50% and 85%, respectively), but higher in fotemustine-treated patients (87.5% and 50%, respectively). OS rates at 9 months were 37.9% (95% CI, 25.5–51.6) and 46.7% (95% CI, 28.3–65.7) with bevacizumab and fotemustine, respectively, and median OS was 7.3 months (95% CI, 5.8–9.2) and 8.7 months (95% CI, 6.3–15.4), respectively. Toxicity was as expected with the 2 agents.

Conclusion

Single-agent bevacizumab may have a role in patients with recurrent glioblastoma.

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