Oral health and pathology: a macrophage account.

Macrophages are present in healthy oral mucosa and their numbers increase dramatically during disease. They can exhibit a diverse range of phenotypes characterised as a functional spectrum from pro-inflammatory to anti-inflammatory (regulatory) subsets. This review illustrates the role of these subsets in the oral inflammatory disease lichen planus, and the immunosuppressive disease oral squamous cell carcinoma (SCC). We conclude that the role of macrophages in driving progression in oral disease identifies them as potential therapeutic targets for a range of oral pathologies

The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM

Cerebral oxidative stress and microvasculature defects in TNF-α expressing transgenic and Porphyromonas gingivalis-infected ApoE-/- mice

The polymicrobial dysbiotic subgingival biofilm microbes associated with periodontal disease appear to contribute to developing pathologies in distal body sites, including the brain. This study examined oxidative stress, in the form of increased protein carbonylation and oxidative protein damage, in the tumour necrosis factor-α (TNF-α) transgenic mouse that models inflammatory TNF-α excess during bacterial infection; and in the apolipoprotein knockout (ApoE-/-) mouse brains, following Porphyromonas gingivalis gingival monoinfection. Following 2,4-dinitrophenylhydrazine derivatization, carbonyl groups were detected in frontal lobe brain tissue lysates by immunoblotting and immunohistochemical analysis of fixed tissue sections from the frontotemporal lobe and the hippocampus. Immunoblot analysis confirmed the presence of variable carbonyl content and oxidative protein damage in all lysates, with TNF-α transgenic blots exhibiting increased protein carbonyl content, with consistently prominent bands at 25 kDa (p = 0.0001), 43 kDa and 68 kDa, over wild-type mice. Compared to sham-infected ApoE-/- mouse blots, P. gingivalis-infected brain tissue blots demonstrated the greatest detectable protein carbonyl content overall, with numerous prominent bands at 25 kDa (p = 0.001) and 43 kDa (p = 0.0001) and an exclusive band to this group between 30-43 kDa* (p = 0.0001). In addition, marked immunostaining was detected exclusively in the microvasculature in P. gingivalis-infected hippocampal tissue sections, compared to sham-infected, wild-type and TNF-α transgenic mice. This study revealed that the hippocampal microvascular structure of P. gingivalis-infected ApoE-/- mice possesses elevated oxidative stress levels, resulting in the associated tight junction proteins being susceptible to increased oxidative/proteolytic degradation, leading to a loss of functional integrity

Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease

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Synergistic effects of bombesin and epidermal growth factor on cancers.

Bombesin and gastrin-releasing peptide act as autocrine mitogens in various cancers. Bombesin antagonist RC-3095 inhibited growth in some cancers and slowed the progression of premalignant lesions, possibly by down-regulating epidermal growth factor (EGF) receptors. Since the EGF receptor mitogen response involves tyrosine kinase stimulation, we tested the hypotheses that bombesin stimulates, and RC-3095 inhibits, phosphorylation; EGF and bombesin promote the phosphorylation of the same substrates; and EGF and bombesin act synergistically on phosphorylation. Therefore, in vitro assays for phosphorylation were performed in the presence or absence of EGF, bombesin, RC-3095, and combinations in samples derived from tumor, tissue surrounding tumor, cell lines, and normal and transforming tissue derived from the 9,10-dimethyl-1,2-benzanthracene-induced squamous cell lesions of the hamster cheek pouch. Bombesin increased, and RC-3095 decreased, phosphorylation in these samples. In the human hepatoma sample and surrounding tissue, these ligands altered the phosphorylation of the same substrates affected by EGF. EGF and bombesin stimulated phosphorylation synergistically in the hamster samples and the hepatoma. Bombesin-induced phosphorylation was greater in tissue surrounding the hepatoma, whereas RC-3095 was more effective in inhibiting phosphorylation in the hepatoma itself. This cancer, therefore, could be endogenously stimulated by gastrin-releasing peptide. These observations support the hypothesis that bombesin stimulates growth of tissues and tumors by amplifying the phosphorylation response to EGF. The growth inhibitory response to RC-3095, or other bombesin analogues, of individual tumors may be prognosed by in vitro phosphorylation assays using the samples from the patient's tumor

Rabbit and Human Non-Keratinising Stratified Squamous Oesophageal Epithelium Displays Similar Microridge Structure by Scanning Electron Microscopy

Since the oesophageal epithelium of common laboratory animals, rats and mice, is keratinized it is unsuitable for comparison with typical non-keratinized stratified squamous human epithelium. It is thus important to find a suitable animal model for the study of human oesophageal tissue changes. This study investigated the microridge structure of immature and adult rabbit specimens, and adult human biopsies by scanning electron microscopy and morphometry. The investigation revealed a similarity between typical squamous human and adult rabbit oesophageal mucosal epithelium. While human epithelium specimens subdivided into two other groups (non-typical squamous and non-squamous); all typical squamous human biopsies were from patients who had normal endoscopy reports and no reflux symptoms. The surface cells of typical squamous human epithelium displayed complex microridge patterns (64% of cell surface) but patterns in non-typical squamous specimens were more variable (38%) (P \u3c 0.001) and cell boundaries less obvious. Rabbit squames displayed clear microridge patterns with an elevation in the percentage of cell surface covered by microridges, with increasing age, from immature to adult specimens (P \u3c 0.001). There was no statistically significant differences between adult rabbit, and \u27typical squamous\u27 human biopsies (range 51-65%), results which suggest potential use of a rabbit model to study changes in human oesophageal tissue

Longitudinal Patterns of Mexican and Puerto Rican Children’s Asthma Controller Medication Adherence and Acute Healthcare Utilization

Rationale: Researchers tend to study Latinos as a single group but recent asthma research confirmed differences among Latino subgroups. Variations in controller medication adherence may be a factor in the observed health disparities between Mexican and Puerto Rican children. Adherence is not a stable phenomenon, however, there is a paucity of data on patterns of adherence, sociodemographic predictors of patterns, and variations in asthma-related acute healthcare utilization by adherence pattern among Latino sub-groups. Objectives: Identify patterns of inhaled corticosteroid medication adherence over twelve months among Mexican and Puerto Rican children with persistent asthma; examine sociodemographic predictors of adherence patterns by ethnicity; and investigate asthma-related acute healthcare utilization based on these patterns. Methods: We analyzed controller medication Doser data from Mexican and Puerto Rican children (n=123; ages 5-12 years) with persistent asthma who participated with their caregivers in a longitudinal, non-intervention study (Phoenix, AZ and Bronx, NY). Interview and medical record data were collected at enrollment, 3, 6, 9, and 12 months post-enrollment. Results: 47%-53% of children had poor adherence ( Conclusions: This study demonstrated that unique ethnicity within Latino populations may be associated with different risk levels for suboptimal controller medication adherence which may be a factor in the observed asthma health disparities between Mexican and Puerto Rican children. Increased understanding of and attention to children’s controller medication adherence patterns will provide evidence needed to identify children at highest risk for acute healthcare utilization and offer more intensive intervention using less-intensive approaches for those at low risk

The effect of habitat composition on sexual conflict in the seaweed flies Coelopa frigida and C. pilipes

Despite the recent explosion of interest in sexual conflict, the effect of environmental conditions on the intensity of sexual conflict within populations has been largely ignored. Reproductive encounters within coelopids are characterized by sexual conflict in the form of intense harassment by males, usually resulting in a vigorous premating struggle. We investigated the effect of habitat composition and duration of exposure to oviposition sites on the level of sexual harassment by males and mating success in two species of European seaweed flies, Coelopa frigida and C. pilipes. The wrack beds inhabited by these two species are dominated by two genera of brown algae, Fucus and Laminaria, the relative proportions of which can vary considerably between wrack beds. Fucus is known to stimulate harassment by males, increase copulation duration and induce females to oviposit in both species. In this study Laminaria stimulated a higher level of harassment by male C. frigida than Fucus did. However, a similar effect was not observed in C. pilipes, with the main additional factor affecting harassment in this species being the age of the male. Our study highlights the potential importance of environmental conditions on the intensity of sexual conflict within a population. We discuss the evolutionary significance of these observed effects in seaweed flies