ABSTRACT
AIMS: Glioblastoma multiforme (GBM) is the most devastating malignant primary brain tumor known. Life expectance is around 15 months after diagnosis. Several events contribute to the GBM progression such as uncontrolled genetic cancer cells proliferation, angiogenesis (mostly vascular endothelial growth factor (VEGF)-mediated), tissue invasion, glioma stem cell activity, immune system failure, and a hypoxic and inflammatory tumor microenvironment. Tumor cells antiproliferative effect of 20 nm citrate-covered gold nanoparticles (cit-AuNP) has been reported, along with anti-inflammatory and anti-oxidative effects. We aimed to test whether either chronic treatment with 20 nm cit-AuNP or anti-VEGF antibody (Ig)-covered AuNP could reduce GBM progression in mice. MAIN METHODS: Effect of the gold nanoparticles on the GL261 glioblastoma cells proliferation in vitro, and on the GL261-induced glioblastoma cell growth in C57BL/6 mice in vivo were tested. Besides, fluorophore-conjugated gold nanoparticles penetration through the GL261 plasma cell membrane, gold labelling in brain parenchyma of glioblastoma-carrying mice, and VEGF expression into the tumor were evaluated. KEY FINDINGS: We observed cit-AuNP did no change the GL261 cells proliferation. Similarly, we demonstrated chronic treatment with either cit-AuNP or anti-VEGF Ig-covered AuNP did not modify the GL261 cells-induced GBM progression in mice. By the end, we showed AuNPs did not trespass in appreciable amount both the GL261 plasma cell membrane and the tumoral blood brain barrier (BBB), and did not change the VEGF expression into the tumor. SIGNIFICANCE: 20 nm cit-AuNP or anti-VEGF Ig covered-AuNP are not good tools to reduce GBM in mice, probably because they do not penetrate both tumor cells and BBB in enough amount to reduce tumor growing.
ABSTRACT
Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women's age and the onset of therapy initiation. In this study, we aimed to determine how vascular senescence and the onset of estrogen treatment influence the common carotid artery (CCA) function in senescent and non-senescent females. Ovariectomized female senescence-accelerated (SAMP8) or non-senescent (SAMR1) mice were treated with vehicle (OVX) or 17ß-estradiol starting at the day of ovariectomy (early-onset, E2E) or 45 days after surgery (late-onset, E2L). In SAMR1, both treatments, E2E and E2L, reduced constriction to phenylephrine (Phe) in CCA [(AUC) OVX: 193.8 ± 15.5; E2E: 128.1 ± 11.6; E2L: 130.2 ± 15.8, p = 0.004] in association with positive regulation of NO/O2- ratio and increased prostacyclin production. In contrast, E2E treatment did not modify vasoconstrictor responses to Phe in OVX-SAMP8 and, yet, E2L increased Phe vasoconstriction [(AUC) OVX: 165.3 ± 10; E2E: 183.3 ± 11.1; E2L: 256.3 ± 30.4, p = 0.005]. Increased vasoconstriction in E2L-SAMP8 was associated with augmented thromboxane A2 and reduced NO production. Analysis of wild-type receptor alpha (ERα66) expression and its variants revealed an increased expression of ERα36 in E2L-SAMP8 in correlation with unfavorable effects of estrogen in those animals. In conclusion, estrogen exerts beneficial effects in non-senescent CCA, regardless of the initiation of the therapy. In senescent CCA, however, estrogen loses its beneficial action even when administered shortly after ovariectomy and may become detrimental when given late after ovariectomy. Aging and onset of estrogen treatment are two critical factors in the mechanism of action of this hormone in CCA.
Subject(s)
Aging , Carotid Arteries/physiopathology , Estrogen Receptor alpha/genetics , Estrogens/adverse effects , Prostaglandins/metabolism , Vasoconstriction , Animals , Carotid Arteries/metabolism , Estrogens/therapeutic use , Female , Gene Expression Regulation , MiceABSTRACT
Recent studies investigating protease-activated receptor type 2 (PAR-2) suggest an association between the receptor and periodontal inflammation. It is known that gingipain, a bacterial protease secreted by the important periodontopathogen Porphyromonas gingivalis can activate PAR-2. Previous studies by our group found that PAR-2 is overexpressed in the gingival crevicular fluid (GCF) of patients with moderate chronic periodontitis (MP). The present study aimed at evaluating whether PAR-2 expression is associated with chronic periodontitis severity. GCF samples and clinical parameters, including plaque and bleeding on probing indices, probing pocket depth and clinical attachment level, were collected from the control group (n = 19) at baseline, and from MP patients (n = 19) and severe chronic periodontitis (SP) (n = 19) patients before and 6 weeks after periodontal non-surgical treatment. PAR-2 and gingipain messenger RNA (mRNA) in the GCF of 4 periodontal sites per patient were evaluated by Reverse Transcription Polymerase Chain Reaction (RT-qPCR). PAR-2 and gingipain expressions were greater in periodontitis patients than in control group patients. In addition, the SP group presented increased PAR-2 and gingipain mRNA levels, compared with the MP group. Furthermore, periodontal treatment significantly reduced (p <0.05) PAR-2 expression in patients with periodontitis. In conclusion, PAR-2 is associated with chronic periodontitis severity and with gingipain levels in the periodontal pocket, thus suggesting that PAR-2 expression in the GCF reflects the severity of destruction during periodontal infection.
Subject(s)
Chronic Periodontitis/pathology , Gingival Crevicular Fluid/chemistry , Receptor, PAR-2/analysis , Adhesins, Bacterial/analysis , Adult , Biomarkers/analysis , Case-Control Studies , Cysteine Endopeptidases/analysis , Dental Plaque Index , Female , Gene Expression , Gingipain Cysteine Endopeptidases , Humans , Male , Middle Aged , Periodontal Attachment Loss , Periodontal Index , Porphyromonas gingivalis , Reference Values , Severity of Illness Index , Statistics, NonparametricABSTRACT
Abstract Recent studies investigating protease-activated receptor type 2 (PAR-2) suggest an association between the receptor and periodontal inflammation. It is known that gingipain, a bacterial protease secreted by the important periodontopathogen Porphyromonas gingivalis can activate PAR-2. Previous studies by our group found that PAR-2 is overexpressed in the gingival crevicular fluid (GCF) of patients with moderate chronic periodontitis (MP). The present study aimed at evaluating whether PAR-2 expression is associated with chronic periodontitis severity. GCF samples and clinical parameters, including plaque and bleeding on probing indices, probing pocket depth and clinical attachment level, were collected from the control group (n = 19) at baseline, and from MP patients (n = 19) and severe chronic periodontitis (SP) (n = 19) patients before and 6 weeks after periodontal non-surgical treatment. PAR-2 and gingipain messenger RNA (mRNA) in the GCF of 4 periodontal sites per patient were evaluated by Reverse Transcription Polymerase Chain Reaction (RT-qPCR). PAR-2 and gingipain expressions were greater in periodontitis patients than in control group patients. In addition, the SP group presented increased PAR-2 and gingipain mRNA levels, compared with the MP group. Furthermore, periodontal treatment significantly reduced (p <0.05) PAR-2 expression in patients with periodontitis. In conclusion, PAR-2 is associated with chronic periodontitis severity and with gingipain levels in the periodontal pocket, thus suggesting that PAR-2 expression in the GCF reflects the severity of destruction during periodontal infection.