Prevents Plaque Formation Research Articles

Clinical and laboratory evaluation of the Elgydium Protection caries toothpaste effectiveness in patients with high intensity of dental caries

The aim of the work was to evaluate the effectiveness of rehabilitation after the complete elimination of carious cavities in patients with dentin caries according to clinical and laboratory indicators when using the ELGYDIUM Protection caries toothpaste for cleaning teeth for 6 months. 29 patients with high intensity of dental caries were examined and received treatment. Depending on the organization of daily hygienic measures after treatment the patients were divided into two groups. The main group included 14 patients who used Elgydium Protection caries paste ('Pierre Fabre Medicament', France) for brushing their teeth twice a day for 6 months. The control group included 15 patients who used toothpastes with fluoride of the first generation. All patients underwent clinical dental examination with the determination of the DMFT index and the amount of soft dental plaque according to the Silness-Lohe index, as well as in the gingival fluid bacteriological examination of cariogenic microbiota, determination of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) and an immunoassay for anti-inflammatory peptides α-defensins 1-3. Effective change in the concentration of antimicrobial peptides α-defensins 1-3 and TNF-α after treatment along with successful eradication of cariogenic bacteria from carious cavities, the absence of recurrent dental caries in the main group compared with the control group proved the successful anti-caries action of long-term use of fluorenol capable of forming a uniform film on the surface of the tooth in the presence of silyglycol. The protective film helps to increase the resistance of the tooth to demineralization and prevents plaque formation. Thus, the study results proved the effectiveness of ELGYDIUM Protection caries toothpaste used for 6 months for the reduction of caries.

Virtual screening following rational drug design based approach for introducing new anti amyloid beta aggregation agent.

Amyloid β (Aβ) sheets aggregations is the main reason of Alzheimer disease. The interacting areas between monomers are residue number 38 to 42. Inhibition of interaction between Aβ molecules prevents plaque formation. In the present study, we have performed a high-throughput virtual screening among ZINC database and top 1000 hits were checked again regarding binding affinity by AutoDock software. Top 4 successive second step screening hits was considered for drug design purpose against aggregation site of Aβ molecules. The toxicity and pharmacological properties of new designed ligands was assessed by PROTOX and FAFdrugs3 webservers. Several steps of modifications performed in the structures of hit#1 and hit#2 and finally new designed ligand based on hit 1, 1-RD-3 (3-[(Z)-6-Hydroxy-4-{[5-(2-methoxyethyl)-6-methyltetrahydro-2H-pyran-2-yl]methyl}-1-methyl-3-hexenyloxy]tetrahydro-2Hpyran- 4-ol) and a designed ligand based on hit 2, 2-RD-2 (6-(Hydroxymethyl)-4-{5-hydroxy-6-methyl-4-[(3- methylcyclohexyl)methyl]tetrahydro-2H-pyran-2-yloxy}tetrahydro-2H-pyran-2,3,5-triol) could successfully pass pharmacological filters. The LD50 of 37000 mg/kg for 1-RD-3 and 2000 mg/kg for 2-RD-2 indicates that the designed ligands can be considered as new candidates for anti Aβ aggregation to treat Alzheimer’s disease. Interestingly, after performing several modification steps still a considerable binding affinity of -9.3 kcal/mol for 1-RD-3 and -9.8 kcal/mol for 2-RD-2 still remained. Theoretically, the new designed molecules can reduce the deposition of Aβ in the cerebral cortex and as the results the Alzheimer symptoms could be decreased.

Bilirubin Inhibits the Transmigration of Monocytes Across Endothelial Cell Monolayers: Implications for Atherosclerosis Prevention

Monocyte infiltration into the vascular endothelium, a critical early step in the formation of atherosclerotic plaques, is mediated primarily by the binding of α and β integrins to endothelial cell adhesion molecules Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intercellular Adhesion Molecule-1 (ICAM-1). Our lab previously has shown that bilirubin, a potent, chain-breaking antioxidant, disrupts VCAM-1-dependent processes by scavenging reactive oxygen species (ROS) signaling intermediates. Therefore, we examined the effect of bilirubin on the transmigration of THP-1 human monocytic cells across TNF-α-activated human umbilical vein endothelial cell (HUVEC) monolayers. Bilirubin, at physiological concentrations (0 – 20 µM) was found to inhibit the movement of THP-1 cells across HUVEC monolayers in a dose-dependent manner. Bilirubin did not alter endothelial cell expression of VCAM-1 or ICAM-1 in response to TNF-α, nor did it inhibit the binding of THP-1 cells to HUVEC monolayers, supporting that bilirubin exerts its effect at the level of cellular transmigration. Studies employing blocking antibodies support that VCAM-1 is the principal adhesion molecule mediating monocyte transmigration. In light of epidemiological studies demonstrating an inverse association between serum bilirubin levels and the risk of cardiovascular disease, we speculate that bilirubin prevents plaque formation by inhibiting monocyte migration across the vascular endothelium through disruption of VCAM-1 signaling.

8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, has been recently rediscovered to inhibit Rac1 in neutrophils and macrophages, thereby inhibiting Rac1-linked functions of these cells, including reactive oxygen species production through NADPH oxidase activation, phagocytosis, chemotaxis, and cytokine release. In vascular smooth muscle cells (VSMCs), reactive oxygen species also induce abnormal proliferation and migration leading to progression of atherosclerosis. Based upon the involvement of reactive oxygen species in phagocytic cells and VSMCs during the atherosclerotic process, we hypothesized that 8-OHdG could have antiatherosclerotic action and tested this hypothesis in an experimentally induced atherosclerosis in mice. Partially ligated ApoE knockout mice, a more physiologically relevant model of low and oscillatory flow, developed an advanced lesion in 2 weeks, and orally administered 8-OHdG significantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infiltration, and extracellular matrix (ECM) accumulation. The effects of 8-OHdG observed in primary VSMCs were consistent with the in vivo effects of 8-OHdG and were inhibitory to angiotensin II or platelet-derived growth factor-induced production of reactive oxygen species, proliferation, migration, and ECM production. Also, angiotensin II-induced Rac1 activity in VSMCs was significantly inhibited by 8-OHdG, and transfection of constitutively active Rac1 reversed the inhibitory effect of 8-OHdG on VSMC activation. Molecular docking study showed that 8-OHdG stabilizes Rac1–GEF complex, indicating the physical contact of 8-OHdG with Rac1. These findings highly suggest that the antiatherosclerotic effect of 8-OHdG is mediated by inhibition of Rac1 activity. In conclusion, our results show a novel action of orally active 8-OHdG in suppressing atherosclerotic plaque formation in vivo and VSMC activation in vitro through inhibition of Rac1, which emphasizes a new therapeutic avenue to benefit atherosclerosis.

O4‐08‐08: Progranulin gene therapy prevents plaque formation and synapse loss in a rodent model of AD

Progranulin (PGRN) is a multifunctional secreted protein expressed primarily by neurons and microglia. Evidence suggests that PGRN may function as a neurotrophic factor and may be essential for long-term neuronal survival, actively protecting neuronal cells from premature death. It also appears to be important for regulating neuroinflammation, consistent with its localization in microglial cells. Loss-of-function mutations in the PGRN gene have been identified as the cause of some forms of fronto-temporal dementia and mutations in PGRN have also been associated with AD and Lewy Body Dementia. Upregulated expression of PGRN has been reported in numerous neurodegenerative diseases involving microglial activation, including motor neuron disease, lysosomal storage disease, and Alzheimer's disease. In light of its role as a neurotrophic factor, this upregulation may represent an attempt to repair damage and protect cells. Here, we present data describing the effects of ND-602, a proprietary construct designed to target PGRN synthesis. The Tg2576 mouse model of AD expresses the Swedish mutation of APP (APPK67ON,M671L) at high levels under the control of the hamster prion protein promoter. These mice develop a progressive, age-related deposition in the form of amyloid plaques in the cortex and hippocampus. A rapid increase in insoluble Aß occurs around 6 months of age and plaques begin to form around 8-12 months of age, resulting in the development of memory deficits. At 8 months of age, Tg2576 mice received unilateral intracerebral injection of either a progranulin-expressing lentiviral vector (ND-602), or a control vector expressing green fluorescent protein (GFP), into the left dorsal hippocampus. At 12 months of age, animals were sacrificed and the brains assessed for pathology. ND-602 was capable of elevating PGRN expression in the dorsal hippocampus, frontal cortex, and entorhinal cortex. Elevations in PGRN expression were associated with increased neprilysin expression, reduced plaque burden, decreased neuroinflammation, and preservation of synapses. Together, the data reported here indicate that ND-602 treatment regulates Aß, a key causal factor in AD, by reducing tissue levels in Tg2576 mice as well as plaque deposition. Thus, ND-602, by targeting PGRN, may represent a potential therapy designed to slow or halt disease progression in AD. Hippocampal β-amyloid burden following lentiviral delivery. (A) Representative photomicrographs depicting β-amyloid immunolabeling in the hippocampal dentate gyrus of a Tg2576 mouse brain 6 months following unilateral intracerebral administration of either LV-GFP, or LV-PGRN (ND-602). (B) Amyloid burden was significantly reduced in the ipsilateral dentate gyrus of those animals receiving ND-602 administration. Each bar represents the mean (± S.E.M.) (n = 10) amyloid burden (% area) measured across 4 coronal sections. ∗∗ sig. diff. from GFP-treated controls, p<0.001.

T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice

BackgroundImmunization against amyloid-β (Aβ), the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD), causes a dramatic immune response that prevents plaque formation and clears accumulated Aβ in transgenic mice. In a clinical trial of Aβ immunization, some patients developed meningoencephalitis and hemorrhages. Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization.ResultsTo define the impact of T cells on this inflammatory response we used passive immunization and adoptive transfer to separate the effect of IgG and T cell mediated effects on microhemorrhage in APPPS1 transgenic mice. Neither anti Aβ IgG nor adoptively transferred T cells, alone, led to increased cerebrovascular damage. However, the combination of adoptively transferred T cells and passive immunization led to massive cerebrovascular bleeding that ranged from multiple microhemorrhages in the parenchyma to large hematomas.ConclusionsOur results indicate that vaccination can lead to Aβ and T cell induced cerebral micro-hemorrhages and acute hematomas, which are greatly exacerbated by T cell mediated activity.

P1-100: CNI-1493 inhibits Aβ production and prevents plaque formation in an animal model of Alzheimer’s disease

P1-100: CNI-1493 inhibits Aβ production and prevents plaque formation in an animal model of Alzheimer’s disease

Enhanced Proteolysis of β-Amyloid in APP Transgenic Mice Prevents Plaque Formation, Secondary Pathology, and Premature Death

Converging evidence suggests that the accumulation of cerebral amyloid β-protein (Aβ) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Aβ thus represents a novel therapeutic approach to lowering steady-state Aβ levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Aβ levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Aβ-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo.

In vivo activities of GroEL minichaperones.

Fragments encompassing the apical domain of GroEL, called minichaperones, facilitate the refolding of several proteins in vitro without requiring GroES, ATP, or the cage-like structure of multimeric GroEL. We have identified the smallest minichaperone that is active in vitro in chaperoning the refolding of rhodanese and cyclophilin A: GroEL(193-335). This finding raises the question of whether the minichaperones are active under more stringent conditions in vivo. The smallest minichaperones complement two temperature-sensitive Escherichia coli groEL alleles, EL44 and EL673, at 43 degreesC. Although they cannot replace GroEL in cells in which the chromosomal groEL gene has been deleted by P1 transduction, GroEL(193-335) enhances the colony-forming ability of such cells when limiting amounts of GroEL are expressed from a tightly regulated plasmid. Surprisingly, we found that overexpression of GroEL prevents plaque formation by bacteriophage lambda and inhibits replication of the lambda origin-dependent plasmid, Lorist6. The minichaperones also inhibit Lorist6 replication, but less markedly. The complex quaternary structure of GroEL, its central cavity, and the structural allosteric changes that take place on the binding of nucleotides and GroES are not essential for all of its functions in vivo.

Selection of lambda Spi − transducing phages using the P2 old gene cloned onto a plasmid

The old gene product of the P2 prophage interferes with plaque formation by λ wild type phage but allows λ phages whose red and gam genes have been deleted to form small, visible plaques (the λ Spi − phenotype). The old gene product also kills Escherichia coli recB or recC mutants. We have cloned the old gene into the high-copy-number plasmid pBR322, where it prevents plaque formation by both λSpi + and λASpi − phages. We transferred a DNA fragment that carries the old gene to the low-copy-number plasmid pSClOl and found that λSpi − phages can be selected on strains that carry this plasmid. The plasmid-bome old gene kills E. coli recB mutants, providing a selection for old − mutants.

Effect of some metabolic inhibitors on plaque formation in Jerne plates.

WHEN lymphoid cells from animals producing haemolytic antibody are incubated with target erythrocytes in a semi-solid agar medium, antibody diffuses from the cells containing it and becomes attached to the red cells. If complement is added after this incubation, the presence of antibody is shown by the formation of plaques of haemolysis1,2. Killing the cells before incorporating them in agar, or adding metabolic inhibitors such as cyanide2 to the agar before incubation, prevents plaque formation. This has been taken as evidence that the antibody-forming cells in the agar are alive and actively secreting antibody. If this were so it would be possible to investigate the modes of action of some immunosuppressive agents by observing their effects when added to the agar medium.

Duration of protective action of interferon against infection with West Nile virus.

INACTIVATED influenza virus has been shown to inhibit the growth of western equine encephalitis virus in eggs1 and in the mouse brain2 and it seemed likely, therefore, that interferon, which appears to mediate viral interference3 should also inhibit the growth of viruses of this group. We have found that interferon strongly inhibits the growth of West Nile virus in cultures of chick fibroblasts, and our colleague Dr. J. S. Porterfield has shown4 that it prevents plaque formation by a number of ‘arbor’ viruses, including West Nile and yellow fever viruses. In this paper we describe experiments carried out with West Nile virus, on the duration of the protective action of interferon.