Oleic acid released by sensory neurons inhibits TRPV1-mediated thermal hypersensitivity via GPR40.

Noxious stimuli activate nociceptive sensory neurons, causing action potential firing and the release of diverse signaling molecules. Several peptides have already been identified to be released by sensory neurons and shown to modulate inflammatory responses and inflammatory pain. However, it is still unclear whether lipid mediators can be released upon sensory neuron activation to modulate intercellular communication. Here, we analyzed the lipid secretome of capsaicin-stimulated nociceptive neurons with LC-HRMS, revealing that oleic acid is strongly released from sensory neurons by capsaicin. We further demonstrated that oleic acid inhibits capsaicin-induced calcium transients in sensory neurons and reverses bradykinin-induced TRPV1 sensitization by a calcineurin (CaN) and GPR40 (FFAR1) dependent pathway. Additionally, oleic acid alleviated zymosan-mediated thermal hypersensitivity via the GPR40, suggesting that the capsaicin-mediated oleic acid release from sensory neurons acts as a protective and feedback mechanism, preventing sensory neurons from nociceptive overstimulation via the GPR40/CaN/TRPV1-axis.

Inhibition of TRPM8 function by prostacyclin receptor agonists requires coupling to Gq/11 proteins.

BACKGROUND AND PURPOSE: The TRPM8 ion channel is involved in innocuous cold sensing and has a potent anti-inflammatory action. Its activation by lower temperature or chemical agonists such as menthol and icilin induces analgesic effects, reversing hypersensitivity and reducing chronic pain. On the other hand, prostacyclin (PGI2) enhances pain and inflammation by activating the IP receptors. Due to the critical roles of TRPM8 and IP receptors in the regulation of inflammatory pain, and considering their overlapping expression pattern, we analysed the functional interaction between human TRPM8 and IP receptors. EXPERIMENTAL APPROACH: We transiently expressed human TRPM8 channels and IP receptors in HEK293T cells and carried out intracellular calcium and cAMP measurements. Additionally, we cultured neurons from the dorsal root ganglia (DRGs) of mice and determined the increase in intracellular calcium triggered by the TRPM8 agonist, icilin, in the presence of the IP receptor agonist cicaprost, the IP receptor antagonist Cay10441, and the Gq/11 inhibitor YM254890. KEY RESULTS: Activation of IP receptors by selective agonists (cicaprost, beraprost, and iloprost) inhibited TRPM8 channel function, independently of the Gs-cAMP pathway. The potent inhibition of TRPM8 channels by IP receptor agonists involved Gq/11 coupling. These effects were also observed in neurons isolated from murine DRGs. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate an unusual signalling pathway of IP receptors by coupling to Gq/11 proteins to inhibit TRPM8 channel function. This pathway may contribute to a better understanding of the role of TRPM8 channels and IP receptors in regulating pain and inflammation.

Thermal Nonlinear Klein-Gordon Equation for Nano-/Micro-Sized Metallic Particle-Attosecond Laser Pulse Interaction.

In this study, a rigorous analytical solution to the thermal nonlinear Klein-Gordon equation in the Kozlowski version is provided. The Klein-Gordon heat equation is solved via the Zhukovsky "state-of-the-art" mathematical techniques. Our study can be regarded as an initial approximation of attosecond laser-particle interaction when the prevalent phenomenon is photon-electron interaction. The electrons interact with the laser beam, which means that the nucleus does not play a significant role in temperature distribution. The particle is supposed to be homogenous with respect to thermophysical properties. This theoretical approach could prove useful for the study of metallic nano-/micro-particles interacting with attosecond laser pulses. Specific applications for Au "nano" particles with a 50 nm radius and "micro" particles with 110, 130, 150, and 1000 nm radii under 100 attosecond laser pulse irradiation are considered. First, the cross-section is supposed to be proportional to the area of the particle, which is assumed to be a perfect sphere of radius R or a rotation ellipsoid. Second, the absorption coefficient is calculated using a semiclassical approach, taking into account the number of atoms per unit volume, the classical electron radius, the laser wavelength, and the atomic scattering factor (10 in case of Au), which cover all the basic aspects for the interaction between the attosecond laser and a nanoparticle. The model is applicable within the 100-2000 nm range. The main conclusion of the model is that for a range inferior to 1000 nm, a competition between ballistic and thermal phenomena occurs. For values in excess of 1000 nm, our study suggests that the thermal phenomena are dominant. Contrastingly, during the irradiation with fs pulses, this value is of the order of 100 nm. This theoretical model's predictions could be soon confirmed with the new EU-ELI facilities in progress, which will generate pulses of 100 as at a 30 nm wavelength.

Histological and immunohistochemical study on the apical granuloma.

INTRODUCTION: Periapical granuloma is one of the most frequent periodontal pathology and belongs to the group named as apical periodontitis. MATERIALS AND METHODS: Out of 78 of diagnosed granulomas, we selected samples that we analyzed histologically and immunohistochemically. RESULTS: The histopathological aspect has been dominated by the presence of mononuclear cells of the lymphocyte and plasma cells type, showing the chronic aspect of the apical lesion. Also, we noticed that in the apical granuloma macrophages occur most often. This density of macrophages explains cellular and tissular disruption that occur in apical region of the tooth under the influence of bacterial flora that reached this area, as they have the role to phagocyte pathogens and cell and tissue residues that result from bacterial aggression. The reaction of the plasma cells, determined by their number, has been always associated with the age of the granulomas, and it is more intense in old, neglected granulomas, compared to recent granulomas. CONCLUSIONS: The number and type of immunity cells varies in the apical granuloma accordingly to the age of granuloma.

Root fractures: epidemiological, clinical and radiographic aspects.

Chronic root fractures are a relative frequent dental condition, occurring both in vital teeth and in teeth with root canal treatment, with a difficult and frustrating diagnosis. Two clinical forms are described: crown-root fractures with crown origin and vertical root fractures with root origin. The aim of the study was to determine the prevalence of the root fractured extracted teeth in two dental clinics with different profile [oral rehabilitation (OR) and endodontics (E)] and to present some particular aspects of the root fractures. A retrospective study over a period of five years was performed to determine the number of extracted teeth and the motives for extraction. For root fractured extracted teeth were noted: fracture type, tooth vitality, restoration type. Although the number of the patients with tooth extractions in the five years period was significantly higher in OR clinic than in E clinic, the number of tooth extractions was almost similar. Most of the teeth (70.6%) were extracted for caries complications. The prevalence of the root fractured extracted teeth was 17.93%. In OR clinic, women had more root fractured extracted teeth compared with E clinic, where the number of root fractured extracted teeth was higher in men. Most extracted teeth for root fracture were teeth with prosthetic restorations followed by teeth with root canal treatment and dental fillings. The most extracted teeth for root fracture were maxillary premolars, almost similar for both sexes, followed by mandibular molars. The teeth with least extractions for root fractures were mandibular incisors and mandibular canine.

Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion from a Meckel diverticulum neuroendocrine tumor: case report.

BACKGROUND: Ectopic production of adrenocorticotropic hormone (ACTH) by neuroendocrine tumours (NET) is a rare condition, occult presentations often hampering the diagnosis. Although NET are relatively frequent in the ileon and Meckel diverticulum, we describe the first Cushing's syndrome due to ectopic adrenocorticotropic syndrome (CS-EAS) arising from a Meckel diverticulum. CASE PRESENTATION: A 44-year-old man was admitted with recent onset of diabetes, myopathy, edema and hypokalemic metabolic alkalosis consistent with Cushing's syndrome. Both basal and dynamic laboratory evaluation suggested CS-EAS. Laboratory testing also showed high serum levels of chromogranin A (CgA) and urinary 5-hydroxyindoleacetic acid (5HIAA). Pituitary and neck/thorax/abdomen/pelvis imaging proved to be normal, while somatostatin analogue ((99m)Tc-HYNIC-TOC) scintigraphy revealed increased focalized ileum uptake on the right iliac fossa. Pre-operative ketoconazole and sandostatin treatment controlled the hypercortisolism within a month. Pathological analysis of the resected submucosal 1.8 cm tumour of the Meckel diverticulum and a metastatic local lymph node confirmed a well differentiated neuroendocrine tumour (grade I), whereas immunohistochemistry was positive for ACTH, chromogranin A and synaptophysin. Post-operative clinical and biochemical resolution of Cushing's syndrome was followed by normalization of both CgA and 5HIAA, which were maintained at the 6 month follow-up. CONCLUSION: The identification, characterization and follow-up of this rare cause of ectopic ACTH secretion is important in order to assess the long-term prognostic and management.