Pharmacological targeting of histamine H4 receptor in periodontal disease.

OBJECTIVE: The objective of this study was to investigate whether histamine H4 receptor (H4 R) antagonists could prevent experimental periodontitis (EP)-induced histological, functional and inflammatory alterations in submandibular gland (SMG), periodontal bone and gingiva. METHODS: Bilateral EP was induced for 2 weeks in anaesthetized male rats. The effect of systemic and local administration of H4 R antagonists (JNJ7777120, JNJ10191584) on histopathology and functionality of SMG, bone loss and gingival inflammation was evaluated. RESULTS: The subcutaneous administration of JNJ7777120 prevented periodontitis-induced SMG histological injury, reducing vacuolization and apoptosis and additionally reversed the increased prostaglandin E2 (PGE2) levels in SMG while it partially reversed the methacholine-induced salivation reduction produced by periodontitis. JNJ7777120 attenuated bone loss and the increased PGE2 levels and inflammatory infiltration in gingival tissue of rats with periodontitis. Finally, local administration of JNJ7777120 and JNJ10191584 was also beneficial for improving periodontal parameters. CONCLUSIONS: H4 receptor antagonists are able to ameliorate periodontitis-induced injury on SMG, gingival tissue and bone structure, suggesting that pharmacological targeting of H4 R could be an attractive strategy to improve periodontal health.

Defining the role of MRP-mediated efflux and glutathione in detoxification of oxaliplatin.

Albeit platinum complexes are widely used in cancer chemotherapy, their cellular processing has not been completely elucidated so far. In this study the effects of modulating multidrug resistance-associated protein (MRP)-mediated efflux and glutathione (GSH) depletion on the cytotoxicity of oxaliplatin were assessed in a human ileocecal colorectal adenocarcinoma cell line and its oxaliplatin-resistant variant. Upon oxaliplatin exposure, DNA platination was elevated by co-incubation with Gü83, a MRP1 and MRP2 inhibitor, but cytotoxicity was not increased. Addition of oxaliplatin did not alter the cellular GSH content. Following GSH depletion, platinum accumulation was unchanged but cytotoxicity was increased in oxaliplatin-sensitive cells. In conclusion, modulation of MRP-mediated efflux did not affect oxaliplatin cytotoxicity in the investigated cell lines. Intracellular GSH depletion seems to sensitize the cells but does not overcome resistance.

Adrenal gland responses to lipopolysaccharide after stress and ethanol administration in male rats.

All forms of stress, including restraint stress (RS) and lipopolysaccharide (LPS) administration, activate the hypothalamic-pituitary-adrenal (HPA) axis. LPS binds to a recognition protein (CD14) and toll-like receptor 2/4 in different cells and tissues, including the adrenal gland, to induce the production of cytokines and cause upregulation of cyclooxygenase and nitric oxide synthase (NOS) enzymes. Acute ethanol exposure activates the HPA axis, but in some conditions prolonged administration can dampen this activation as well as decrease the inflammatory responses to LPS. Therefore, this study was designed to evaluate the adrenal response to a challenge dose of LPS (50 µg/kg) injected i.p., after submitting male rats to RS, twice a day (2 h each time) for 5 days and/or ethanol administration (3 g/kg) by gavage also for 5 days, twice daily. At the end of the experiment, plasma corticosterone concentrations and adrenal gland content of prostaglandin E (PGE) and NOS activity were measured as stress mediators. The results showed that repetitive ethanol administration attenuated the adrenal stress response to LPS challenge alone and after RS, by preventing the increase in plasma corticosterone concentrations and by decreasing the PGE content and NOS activity in the adrenal gland. Therefore, we conclude that moderate alcohol consumption could attenuate the effects of psychophysical stress and impair an inflammatory response.

Expression and function of endocannabinoid receptors in the human adrenal cortex.

Endogenous cannabinoids are important signaling molecules in neuroendocrine control of homeostatic and reproductive functions including stress response and energy metabolism. The hypothalamic paraventricular and supraoptic nuclei have been shown to release endocannabinoids, which act as retrograde messengers to modulate the synaptic release of glutamate during stress response. This study endeavors to elucidate possible interaction of the endocannabinoid system with the regulation of adrenocortical function at the adrenal level. Human adrenocortical NCI-H295R cells and normal human adrenal glands were used to study the possible effects of anandamide and cannabinoid receptor 1 (CB1) antagonist SR141716A on aldosterone and cortisol secretion. Our data indicate the expression of CB1 in human adrenal cortex and adrenocortical NCI-H295R cells; CB2 was not expressed. Furthermore, anandamide inhibited basal release and stimulated release of adrenocortical steroids (corticosterone and aldosterone); this effect was reversed by CB1 antagonist (SR141716A). Therefore, the endocannabinoid system at the level of the adrenal, can directly influence adrenocortical steroidogenesis.

Fractionation of an anthocyanin-rich bilberry extract and in vitro antioxidative activity testing.

The incidence of chronic diseases increases with advancing age of the population. A commonly discussed cause of chronic diseases is oxidative stress, which occurs in the body when there is an imbalance between the formation and inactivation of so-called reactive oxygen species (ROS). Epidemiological data suggest that a 'healthy diet', with a high content of flavonoids indicates preventive properties and correlates with an inverse effect with respect to the risk of chronic diseases. Berries (especially bilberries, Vaccinium myrtillus L.) are an important source of these flavonoids. In this study, we investigated, in vitro, the antioxidative properties of fractions obtained from a commercially available anthocyanin-rich bilberry extract (BE). As markers for antioxidative activity, the intracellularly generated ROS levels, oxidative DNA damage, and total glutathione (tGSH) levels were determined in the human colon cell lines Caco-2 and HT-29. In Caco-2 cells, the ROS levels and, in both cell lines, the oxidative DNA damage, were significantly reduced in the presence of the original BE and phenolcarbonic acid-rich fraction. Total GSH levels were slightly increased after pretreatment with BE, phenolcarbonic acid and the polymeric fractions, but not with the anthocyanin fraction. In summary, the BE and the therefrom-isolated phenolcarbonic acid-rich fraction, showed the most potent antioxidative activity whereas the polymeric and anthocyanin-rich fraction, in total, were less active.

COX and LOX eicosanoids modulate platelet activation and procoagulation induced by two murine cancer cells.

Involvement of arachidonic acid cyclooxygenase (COX) and lipoxygenase (LOX) metabolites in platelet aggregation and coagulation induced by two varieties of cancer cells of murine transplantable tumors was studied. A lung alveolar carcinoma (LAC) and a fibrosarcoma (FS), induced platelet aggregation and plasma coagulation (P<0.05). Pretreatment of both tumor lines with a COX inhibitor did not block the tumor cell induced platelet aggregation (TCIPA). COX [12(S)-HTT] and LOX [12(S)-HETE], metabolites of washed platelets (WP), alone or co-incubated with LAC or FS cells, were analyzed. We observed higher 12(S)-HETE release with respect to 12(S)HHT when WP were co-incubated with LAC cells. With both neoplastic cell (NC) lines prothrombin time (PT) was shortened. Pretreatment of NC with iodoacetic acid, soybean trypsin inhibitor or Factor X-deficient plasma increased the PT. These results indicate that AA metabolites play a role on the procoagulation and platelet aggregation induced by mesenchymal and epithelial murine cancers.

Bilateral condylar movement patterns in adult subjects.

The purpose of this study was to determine if there was a difference between the temporomandibular condylar movement patterns of a symptomatic adult population and those of an asymptomatic adult population. Thirty-five volunteers who were not seeking treatment for TMD underwent two different assessments for TMD signs and symptoms: (1) a self-administered questionnaire and (2) a clinical examination. Based on the information obtained from the questionnaires, subjects were divided into "reported-symptomatic" and "reported-asymptomatic" groups. Based on the investigator's clinically evaluation of the same subjects, subjects were divided into "clinically symptomatic" and "clinically asymptomatic" groups. To compare condylar movement patterns, both groups of subjects then had their mandibular border condylar movements measured bilaterally using a sagittal recording device during maximum opening, maximum protrusion, and maximum left and right excursion movements. The patterns were separated into two broad groups, "symmetric" and "asymmetric." Symmetric gliding movements were defined as uninterrupted bilaterally mirror-like patterns of each condyle with a difference between left and right total length excursion not exceeding 2 mm during opening in the sagittal plane or horizontal plane. Our results show that 63% of the subjects who reported clinically asymptomatic for TMD demonstrated asymmetric condylar movements. However, 100% of the patients (n = 5) who reported clinically symptomatic for TMD exhibited asymmetric condylar movements. This finding suggests that, while a very high percentage of TMD subjects will have asymmetric condylar movements, condylar movements alone are not necessarily diagnostic of TMD, and the sagittal recording device may alert the clinician to abnormal movements.

[Secondary longitudinal melanonychia secondary to onychophagia]. / Mélanonychies longitudinales secondaires à une onychophagie.

BACKGROUND: Melanonychia of the toenails sometimes results from repeated trauma. This etiology is rarely put forward in lesions affecting the fingernails. CASE REPORT: A 44-year-old woman developed melanonychia affecting 9 fingernails. Genetic predisposition and drug, hormonal or infectious causes were ruled out and we postulated that the lesions were induced by nail biting. DISCUSSION: Nail biting is known to lead to several types of lesions, including melanonychia. The lesions may sometimes disappear several months after stopping this habit.

[Chronic depigmentation due to positive patch tests for methacryate derivatives]. / Dépigmentation durable secondaire à des tests positifs aux dérivés des méthacrylates.

INTRODUCTION: Many chemical products are known to induce depigmentation. This phenomenon was never reported with methacrylates which are components of acrylic resine. CASE REPORT: A female patient with artificial nails developed contact dermatitis. Localized depigmentation at the site of positive patch tests to methacrylates derivatives was observed. DISCUSSION: The chemical substance could have a direct influence either by its toxic effect or by the induced inflammatory reaction.

Revisión de los efectos del consumo de alcohol sobre la salud periodontal / A review of the effects of alcohol consumption on periodontal health

La periodontitis es una enfermedad infecciosa caracterizada por la formación de bolsas periodontales que alojan microorganismos patógenos y por la inflamación de los tejidos de soporte dentario, ambas condiciones suman sus efectos nocivos provocando resorción ósea alveolar y deterioro del resto de los tejidos periodontales. La enfermedad se inicia por acumulación de placa bacteriana, pero su patogénesis progresa asociada a la respuesta inmune/inflamatoria del huésped que incrementa el deterioro de los tejidos periodontales. El alcohol es la sustancia de abuso de mayor consumo en todo el mundo. La literatura presenta numerosos estudios de correlación entre consumo de alcohol y desarrollo de enfermedades orales en seres humanos, aunque algunos autores han reportado efectos benéficos del consumo moderado de determinados tipos de alcohol. En este trabajo, luego de una revisión exhaustiva de la literatura, se concluye que el consumo abusivo de alcohol daña los tejidos periodontales y aumenta la predisposición de desarrollar periodontitis. Para finalizar, se describen los principales mecanismos que podrían estar implicados (AU)

Periodontitis is an infectious disease characterized by the formation of periodontal pockets that harbor pathogenic microorganisms and by the inflammation of dental support tissues, both of which add their harmful effects causing alveolar bone resorption and deterioration of the rest of the periodontal tissues. The disease was initiated by the accumulation of bacterial plaque, but its pathogenesis progresses associated with the immune / inflammatory response of the host that increases the deterioration of the periodontal tissues. Alcohol is the most commonly abused substance in the world. The literature presents numerous studies of the correlation between alcohol consumption and development of oral diseases in humans, although some authors have reported beneficial effects of moderate consumption of certain types of alcohol. In this paper, after an exhaustive review of the literature, it is concluded that the abusive consumption of alcohol damages the periodontal tissues and increases the predisposition to develop periodontitis. Finally, the main mechanisms that could be involved were described (AU)

Neutron powder diffraction and molecular dynamics study of superionic SrBr2.

The nature of the dynamic ionic disorder within the high-temperature superionic phase of strontium bromide, ß-SrBr2, has been investigated using reverse Monte Carlo (RMC) modelling of neutron powder diffraction data and complementary ab initio molecular dynamics (MD) simulations. The RMC and MD results are in good agreement and indicate the presence of extensive dynamic disorder within the Br(-) sublattice of the cubic fluorite structure. Rapid anion diffusion predominantly occurs as hops between nearest neighbour sites in the 〈100〉 directions, though the trajectories are markedly curved and pass through the peripheries of the octahedral voids in the cation sublattice. In addition, there are extensive correlations between the motions of individual Br(-), often leading to the formation of a short-lived square antiprism co-ordination environment around the Sr(2+). Such polyhedra are observed within the (ambient temperature) ordered tetragonal crystal structure of α-SrBr2. The nature of the ionic disorder in SrBr2 is of particular interest because it is the only known example of a Br(-)-ion superionic. Owing to the large size of this anion, a comparison with the behaviour of other superionic phases gives an insight into the role of ionic size on the conducting properties within these materials.

Endocannabinoids mediate hyposalivation induced by inflammogens in the submandibular glands and hypothalamus.

OBJECTIVE: The aim of this study was to investigate the factors that could participate on salivary glands hypofunction during inflammation and the participation of endocannabinoids in hyposalivation induced by the presence of inflammogens in the submandibular gland (SMG) or in the brain. DESIGN: Salivary secretion was assessed in the presence of inflammogens and/or the cannabinoid receptor antagonist AM251 in the SMG or in the brain of rats. At the end of the experiments, some systemic and glandular inflammatory markers were measured and histopathological analysis was performed. RESULTS: The inhibitory effect observed 1h after lipopolysaccharide (LPS, 50µg/50µl) injection into the SMG (ig) was completely prevented by the injection of AM251 (5µg/50µl) by the same route (P<0.05). The LPS (ig)-induced increase in PGE2 content was not altered by AM251 (ig), while the glandular production of TNFα induced by the endotoxin (P<0.001) was partially blocked by it. Also, LPS injection produced no significant changes in the wet weight of the SMG neither damage to lipid membranes of its cells, nor significant microscopic changes in them, after hispopathological analysis, compared to controls. Finally, TNFα (100ng/5µl) injected intracerebro-ventricularly (icv) inhibited methacholine-induced salivary secretion evaluated 30min after (P<0.01), but the previous injection of AM251 (500ng/5µl, icv) prevented completely that effect. CONCLUSION: We conclude that endocannabinoids mediate the hyposialia induced by inflammogens in the SMG and in the brain. The hypofunction would be due to changes on signalling pathway produced by inflammatory compounds since anatomical changes were not observed.

Eficacia del monepantel para el control de aislamientos de Haemonchus contortus y Trichostrongylus spp. con resistencia múltiple (ivermectina y febendazole) en caprinos

El monepantel es un nuevo antihelmíntico registrado en nuestro país exclusivamente para el control de los nematodes gastrointestinales de los ovinos y su uso ha sido direccionado mayormente hacia el control de parásitos resistentes a las clases de antihelmínticos disponibles actualmente. Estos mismos nematodes también parasitan a los caprinos, pero en estos rumiantes la patofisiología y la respuesta a los antihelmínticos es diferente, lo cual resulta en un mayor parasitismo y complejidad en el manejo de la resistencia. La presente comunicación informa sobre la eficacia del monepantel en dos hatos caprinos mantenidos bajo condiciones de campo y parasitados naturalmente por los géneros de nematodes gastrointestinales más comunes del área central de la Argentina (Haemonchus y Trichostrongylus) y portando alelos de resistencia múltiple (ivermectina y febendazole). El test de reducción en el conteo de huevos post tratamiento comparando diversas fórmulas, indicaron que en todos los hatos el monepantel por vía oral y a la dosis de 3,75 mg/kg de peso (1,5 veces mayor a la dosis ovina), resultó en eficacias del 99% al 100 %. Se realizan breves consideraciones sobre el uso potencial de esta droga en caprinos.

Monepantel is a new anthelmintic registered in Argentina exclusively for control of gastrointestinal nematodes of sheep and mostly directed toward controlling resistant parasites to current available classes of anthelmintics. The same nematodes also parasitize goats but pathophysiology and response are different in these hosts resulting in more severe parasitism and complexity in handling anthelmintic resistance. This report assess the efficacy of monepantel in goats maintained under field conditions and naturally parasitized by most common gastrointestinal nematodes from central Argentina (Haemonchus and Trichostrongylus) carrying alleles of multiple resistance (ivermectin and febendazole). According to the egg count reduction test, efficacies of 99% to 100% were observed after monepantel treatment at 3.75 mg/kg orally (1.5 ovine dose).

Pam3CSK4 and LTA-TLRs ligands associated with microdomains induce IL8 production in human adrenocortical cancer cells.

Bacterially derived ligands, Pam3CSK4 and LPS, can directly impact adrenal glands steroidogenesis through microdomain-related TLR1/2 and 4, respectively, and indirectly via immune cell-derived cytokines. The bilateral immunoadrenal relationship plays an important role in the proper functioning of both systems. CXC chemokine-dependent immune cell infiltration into adrenocortical carcinomas (ACC), which correlates with poor prognosis, is a common phenomenon. Recently, IL8 was identified in ACC and NCI-H295R cells, and was found to contribute to ACC tumour growth. The aim of this study was to clarify the role of different TLR ligands in IL8 production in NCI-H295R cells. This is the first study to demonstrate the expression of several TLRs including TLR1, 3, 6, 7 and 9 in human adrenocortical cells by using the RT-PCR approach. Only stimulation with TLR1/6 together with TLR2 ligands resulted in IL8 peptide and mRNA induction in a dose and time-dependent manner. Our data suggest that gram-positive bacteria-related TLR1/2/6 ligands might contribute to adrenal gland tumorigenesis via IL8 production.

Astrocytic glutamate uptake and prion protein expression.

Factors influencing glutamate uptake by astrocytes may indirectly influence neuronal survival. Elevated extracellular glutamate may be excitotoxic or may exacerbate neurodegeneration in various neurological diseases. By using a cell culture model, we have investigated the influence of astrocytic prion protein (PrPc) expression on glutamate uptake. Type 1 astrocytes expressing PrPc have a higher rate of Na+-dependent glutamate uptake than PrPc-deficient type 1 astrocytes. This difference is exacerbated when serum free media is used to culture the astrocytes. Further analysis suggested that a decrease in substrate affinity is responsible for the sensitivity of PrP-deficient astrocytic glutamate uptake to culture conditions. PrPc has been shown to bind copper. Greater sensitivity of cells to copper concentrations may be responsible for the decreased substrate affinity observed. PrPc-deficient cerebellar cells are more sensitive to glutamate toxicity in the presence of copper. These results show that glutamate uptake from astrocytes is dependent on PrPc expression which in turn may be related to copper metabolism.

Interaction among beta-endorphin, nitric oxide and prostaglandins during ovulation in rats.

The aim of this study was to investigate the relationship between beta-endorphin and nitric oxide (NO) during the ovulatory process in rats. Immature rats were treated with equine chorionic gonadotrophin-hCG to induce ovulation. An intrabursal injection of beta-endorphin stimulated nitric oxide synthase (NOS) activity. This effect was completely reversed when naltrexone was co-injected with beta-endorphin. The stimulatory action of beta-endorphin on NOS activity was studied to determine whether it was exerted via prostaglandins. Treatment with prostaglandin E(2) (PGE(2)) completely reversed the beta-endorphin-induced stimulation of NOS activity. Moreover, intrabursal injection of meloxicam, an inhibitor of cyclooxygenase 2, increased NOS activity, but this effect was not altered by co-injection with beta-endorphin. The presence of both endothelial NOS (eNOS) and inducible NOS (iNOS) in the ovary at 10 h after hCG treatment was studied by western blot analysis. Local administration of beta-endorphin inhibited the expression of eNOS protein, whereas expression of iNOS protein was not detectable. Ovarian beta-endorphin content was diminished at 10 h after hCG injection. Treatment with prostaglandin synthesis inhibitors in vivo augmented the ovarian beta-endorphin content. In conclusion, these results indicate that beta-endorphin stimulates the activity of ovarian NOS indirectly by inhibiting prostaglandin production.

Inhibition of salivary secretion by lipopolysaccharide: possible role of prostaglandins.

Inducible (calcium-independent) nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are important in the regulation of the function of different organs during infection. A single dose of lipopolysaccharide (LPS; 5 mg/kg ip) within 6 h increased NOS activity (20%) and prostaglandin E (PGE) content (100%) in submandibular glands (SMG) and blocked stimulated salivary secretion in adult male rats. The administration of an iNOS synthesis inhibitor, aminoguanidine (AG), with LPS decreased NOS activity and PGE content. Furthermore, the administration of meloxicam (MLX), an inhibitor of COX-2, blocked the increase in PGE and the production of NO. The incubation of slices of SMG in the presence of 3-morpholinosydnonimine, a donor of NO, increased the release of PGE highly significantly. The incubation of SMG in the presence of a PGE(1) analog (alprostadil) increased the production of NO. These results indicate that LPS activates NOS, leading to NO release, which activates COX, generating PGEs that act back to further activate NOS, causing further generation of PGEs by activation of COX. Because the alprostadil administration inhibited stimulated salivation, LPS-induced inhibition of salivation appears to be caused by increased PGE production. Diminished salivary secretion produces poor oral health; thus the use of COX-2 inhibitors to counteract the effects of inhibited salivation should be considered.

Effects of aminoguanidine and meloxicam on nitric oxide and prostaglandin E production induced by lipopolysaccharide in the hypothalamus and anterior pituitary of the rat.

BACKGROUND/OBJECTIVE: Injection of bacterial lipopolysaccharide (LPS) into male rats activates genes that in turn induce many enzymes that participate in the animals' response to LPS. There is induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in many tissues. This induction could result from combination with cell surface LPS receptors that directly induce both genes, or the nitric oxide (NO) released as a result of iNOS induction could induce COX-2. METHODS: To distinguish between these two possibilities, specific inhibitors of iNOS and COX-2 activity, aminoguanidine (AG) and meloxicam (MLX), respectively, were injected either peripherally or intracerebroventricularly (i.c.v.), and their effect on NO and prostaglandin E (PGE) production induced by LPS in the medial basal hypothalamus (MBH) and anterior pituitary gland (AP) were determined. RESULTS: Peripheral injection of AG blocked iNOS-derived NO production in the AP but not in the MBH. When AG was injected i.c.v., iNOS-derived NO production in the MBH was blocked. MLX injected peripherally blocked COX-2-derived PGE(2) production in the MBH and AP, whereas AG injected peripherally or i.c.v. was ineffective. Since AG was only effective in blocking iNOS-derived NO production in the MBH when injected i.c.v., AG apparently does not effectively cross the blood brain barrier, whereas MLX injected peripherally inhibited PGE production, probably by inhibiting COX-2 activity in both the MBH and AP. AG was ineffective in preventing the increase in PGE derived from COX-2 in either the MBH or AP. CONCLUSION: LPS directly induces both enzymes, iNOS and COX-2, in the hypothalamus and AP.