The TRPM8 antagonist RGM8-51 displays analgesic activity in different pain models

TRPM8 channels are overexpressed in sensory neurons after nerve injury or inflammation, resulting in enhanced sensitivity (allodynia and hyperalgesia) to physical stimulation, and have been implicated in migraine, but the interest of TRPM8 antagonists is still a matter of controversy (1,2). The aim of our work was to evaluate the analgesic activity of a TRPM8 antagonist, RGM8-51, in different pain models, looking for similarities and differences with other antagonists. To this end, we used the mouse oxaliplatin-induced peripheral neuropathy, the chronic constriction injury of the rat sciatic nerve (CCI) and mouse NTG-induced migraine-like models. Compound RGM8- 51 reduces the cold allodynia induced by oxaliplatin, from 15 to 60 min after administration (0.1-1 μg, i.pl.), decreases the nocifensive responses to cold, heat and mechanical stimuli in the CCI model (10 μg, i.pl., 30 mg/Kg, i.p.), and relief chronic pain associated to migraine in mouse, in a sex-dependent manner (10 or 30 mg/Kg, i.v.). The β–lactam derivative RGM8-51 not only has analgesic activity in all assayed animal models, but also seems to have a different mode of interaction with the TRPM8 channel than other antagonists, as suggested by docking studies

Effect of the presence of the plant growth promoting rhizobacterium (PGPR) Chryseobacterium balustinum Aur9 and salt stress in the pattern of flavonoids exuded by soybean roots

In this work we studied how biotic and abiotic stresses can alter the pattern of flavonoids exuded by Osumi soybean roots. A routine method was developed for the detection and characterization of the flavonoids present in soybean root exudates using HPLC-MS/MS. Then, a systematic screening of the flavonoids exuded under biotic stress, the presence of a plant growth promoting rhizobacterium, and salt stress was carried out. Results obtained indicate that the presence of Chryseobacterium balustinum Aur9 or 50 mM NaCl changes qualitatively the pattern of flavonoids exuded when compared to control conditions. Thus, in the presence of C. balustinum Aur9, soybean roots did not exude quercetin and naringenin and, under salt stress, flavonoids daidzein and naringenin could not be detected. Soybean root exudates obtained under saline conditions showed a diminished capacity to induce the expression of the nodA gene in comparison to the exudates obtained in the absence of salt. Moreover, lipochitooligosaccharides (LCOs) were not detected or weakly detected when Sinorhizobium fredii SMH12 was grown in the exudates obtained under salt stress conditions or under salt stress in the presence of C. balustinum Au9, respectively.Fil: Dardanelli, Marta Susana. Universidad de Sevilla. Facultad de Farmacia; España. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Biología Molecular. Sección Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Manyani, Hamid. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: González Barroso, Sergio. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: Rodríguez Carvajal, Miguel A.. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: Gil Serrano, Antonio M.. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: Espuny, Maria R.. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: López Baena, Francisco Javier. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: Bellogín, Ramon A.. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: Megías, Manuel. Universidad de Sevilla. Facultad de Farmacia; EspañaFil: Ollero, Francisco J.. Universidad de Sevilla. Facultad de Farmacia; Españ

β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models

Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases

Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency

Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming ‘‘boosters’’ also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency

Characterization of Tajogaite volcanic plumes detected over the Iberian Peninsula from a set of satellite and ground-based remote sensing instrumentation

Three volcanic plumes were detected during the Tajogaite volcano eruptive activity (Canary Islands, Spain, September–December 2021) over the Iberian Peninsula. The spatiotemporal evolution of these events is characterised by combining passive satellite remote sensing and ground-based lidar and sun-photometer systems. The inversion algorithm GRASP is used with a suite of ground-based remote sensing instruments such as lidar/ ceilometer and sun-photometer from eight sites at different locations throughout the Iberian Peninsula. Satellite observations showed that the volcanic ash plumes remained nearby the Canary Islands covering a mean area of 120 ± 202 km2 during the whole period of eruptive activity and that sulphur dioxide plumes reached the Iberian Peninsula

Synthesis, structure and luminescence of Er3+-doped Y3Ga5O12 nano-garnets

A novel Y3(1-x)Er3xGa5O12 nanocrystalline garnet has been synthesized by a sol-gel technique and a complete structural, morphological, vibrational, and optical characterization has been carried out in order to correlate the local structure of the Er3+ ions with their optical properties. The synthesized nanocrystals are found in a single-phase garnet structure with an average grain size of around 60 nm. The good crystalline quality of the garnet structure is confirmed by FTIR and Raman measurements, since the phonon modes of the nano-garnet are similar to those found in the single crystal garnet. Under blue laser excitation, intense green and red visible and 1.5 mu m infrared luminescences are observed, whose relative intensities are very sensitive to the Er3+ concentration. The dynamics of these emissions under pulsed laser excitations are analyzed in the framework of different energy transfer interactions. Intense visible upconverted luminescence can be clearly observed by the naked eye for all synthesized Er3+-doped Y3Ga5O12 nano-garnets under a cw 790 nm laser excitation. The power dependency and the dynamics of the upconverted luminescence confirm the existence of different two-photon upconversion processes for the green and red emissions that strongly depend on the Er3+ concentration, showing the potential of these nano-garnets as excellent candidates for developing new optical devices.This work has been partially supported by Ministerio de Ciencia e Innovacion of Spain (MICCIN) under The National Program of Materials (MAT2010-21270-C04-02; -03; -04), The Consolider-Ingenio 2010 Program (MALTA CSD2007-0045), and The National Infrastructure Program, by Ministerio de Economia y Competitividad of Spain (MINECO) within The Indo-Spanish Joint Programme of Cooperation in Science and Technology (PRI-PIBIN-2011-1153/DST-INT-Spain-P-38-11), and by the EU-FEDER funds (UCAN08-4E-008). S.F. Leon-Luis and V. Monteseguro wish to thank MICINN for the FPI grants (BES-2008-003353 and BES-2011-044596). Dr V. Venkatramu is grateful to DAE-BRNS, Government of India for the award of DAE Research Award for Young Scientists (no. 2010/20/34/5/BRNS/2223).Venkatramu, V.; León-Luis, SF.; Rodriguez-Mendoza, UR.; Monteseguro, V.; Manjón, FJ.; Lozano-Gorrín, AD.; Valiente, R.... (2012). Synthesis, structure and luminescence of Er3+-doped Y3Ga5O12 nano-garnets. Journal of Materials Chemistry. 22:13788-13799. doi:10.1039/c2jm31386cS13788137992

Selective Decrease of Components of the Creatine Kinase System and ATP Synthase Complex in Chronic Chagas Disease Cardiomyopathy

Chronic Chagas disease cardiomyopathy (CCC) affects millions in endemic areas and is presenting in growing numbers in the USA and European countries due to migration currents. Clinical progression, length of survival and overall prognosis are significantly worse in CCC patients when compared to patients with dilated cardiomyopathy of non-inflammatory etiology. Impairment of energy metabolism seems to play a role in heart failure due to cardiomyopathies. Herein, we have analyzed energy metabolism enzymes in myocardium samples of CCC patients comparing to other non-inflammatory cardiomyopathies. We found that myocardial tissue from CCC patients displays a significant reduction of both myocardial protein levels of ATP synthase alpha and creatine kinase enzyme activity, in comparison to control heart samples, as well as idiopathic dilated cardiomyopathy and ischemic cardiomyopathy. Our results suggest that CCC myocardium displays a selective energetic deficit, which may play a role in the reduced heart function observed in such patients

Proceedings of the Association for Research in Vision and Ophthalmology and Champalimaud Foundation Ocular Oncogenesis and Oncology Conference

Ophthalmic researc