A Methodology for Shielding-Gas Selection in Wire Arc Additive Manufacturing with Stainless Steel.

The main objective of this work was to propose and evaluate a methodology for shielding-gas selection in additive manufacturing assisted by wire arc additive manufacturing (WAAM) with an austenitic stainless steel as feedstock. To validate the proposed methodology, the impact of multi-component gases was valued using three different Ar-based blends recommended as shielding gas for GMA (gas metal arc) of the target material, using CMT (cold metal transfer) as the process version. This assessment considered features that potentially affect the building of the case study of thin walls, such as metal transfer regularity, deposition time, and geometrical and metallurgical characteristics. Different settings of wire-feed speeds were conceived to maintain a similar mean current (first constraint for comparison's sake) among the three gas blends. This approach implied different mean wire-feed speeds and simultaneously forced a change in the deposition speed to maintain the same amount of material deposited per unit of length (second comparison constraint). The composition of the gases affects the operational performance of the shielding gases. It was concluded that by following this methodology, shielding-gas selection decision-making is possible based on the perceived characteristics of the different commercial blends.

Amanhã será um novo dia: SUS presente nos territórios e na vida de Manicoré, AM / Tomorrow will be a new day: SUS present in the territories and lives of Manicoré, AM

O livro que temos em mãos nasce de um momento de participação social que foi a Primeira Mostra de experiências dos trabalhadores e trabalhadoras de saúde do município de Manicoré. O título do livro foi inspirado na 17ª Conferência Nacional de Saúde, realizada em 2023, que teve como tema "Garantir direitos, defender o SUS, a vida e a democracia ­ Amanhã vai ser outro dia!". Portanto, o livro inicia na perspectiva de uma escrita coletiva e participativa, que também podemos denominar de Educação Permanente em Saúde porque houve uma reflexão e uma sistematização sobre o fazer e o saber no contexto do trabalho, percorrendo diferentes caminhos da gestão até as comunidades mais distantes. A caminhada foi coletiva, com muitas mãos, vozes, corpos, rostos, imagens e relatos, ou seja, foi um grande mutirão de produção do conhecimento a partir do lugar do trabalho e da gestão nos mais distintos territórios de Manicoré.

Zirconia Implants Produced by Additive Manufacturing - A Scoping Review.

INTRODUCTION: Additive manufacturing is a tool with potential use in medicine and dentistry. The manufacture of metals and composites is already advanced, however, concerns about titanium hypersensitivity, tissue staining, and corrosion caused by gradual material degradation encourage research into more biocompatible alternatives. OBJECTIVE: This systematic scoping review aimed to gather studies that evaluated zirconia implants produced by additive manufacturing to describe the current stage of the printing technique and the final product. METHODS: Searches in Embase, PubMed, SCOPUS, Web of Science, and Google Scholar databases were enriched with manual searches between February and March 2021 and updated in June 2022 using keywords: zirconium implants, zirconium oxide, additive manufacturing, rapid prototyping, 3D printing, selective laser melting, and electron beam melting. The criteria included studies that evaluated or described zirconia implants obtained by 3D printing, with a direct relationship to dentistry or orthopedics. RESULTS: The database search resulted in 671 articles. Eight articles were selected for full reading and remained in this systematic review. CONCLUSION: The printing technique for zirconia implants is promising. However, further studies are required before implants produced by the printing technique can be tested clinically. The literature with results regarding the impression product is still limited.

The effects of leptin and cannabinoid CB1 receptor agonist/antagonist in cerebral tissues of epileptic rats

SUMMARY OBJECTIVE: In this study, the effects of leptin, cannabinoid-1 (CB1) receptor agonist ACEA and antagonist AM251, and the interactions between leptin and CB1 receptor agonist/antagonist on oxidant and antioxidant enzymes in the cerebrum, cerebellum, and pedunculus cerebri tissue samples were investigated in the penicillin-induced epileptic model. METHODS: Male Wistar albino rats (n=56) were included in this study. In anesthetized animals, 500 IU penicillin-G potassium was injected into the cortex to induce epileptiform activity. Leptin (1 μg), ACEA (7.5 μg), AM251 (0.25 μg), and the combinations of the leptin+ACEA and leptin+AM251 were administered intracerebroventricularly (i.c.v.) after penicillin injections. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels were measured in the cerebral tissue samples and plasma with the ELISA method. RESULTS: MDA levels increased, while SOD and GPx levels decreased after penicillin injection in the cerebrum and cerebellum. The efficacy of penicillin on SOD, MDA and GPx levels was further enhanced after leptin or AM251 injections. Whereas, ACEA decreased the MDA levels and increased GPx levels compared with the penicillin group. Administration of AM251+leptin did not change any oxidation parameter compared with the AM251. Furthermore, co-administration of ACEA and leptin significantly increased oxidative stress compared with the ACEA-treated group by increasing MDA and decreasing GPx levels. CONCLUSION: It was concluded that leptin reversed the effect of ACEA on oxidative stress. Co-administration of AM251 and leptin did not change oxidative stress compared with the AM251-treated group suggesting AM251 and leptin affect oxidative stress using the same pathways.

Clinical and prognostic significance of CD27 and CD44 expression patterns in Egyptian pediatric patients with B-precursor acute lymphoblastic leukemia.

INTRODUCTION: The expression pattern of CD27 and CD44 was found to correlate with the differentiation stages of B cell precursors, which were known to be involved in a variety of immunological responses. AIM OF THE STUDY: This study aimed to determine the biological significance of CD27 and CD44 expression in patients with B-precursor acute lymphoblastic leukemia (B-ALL), as well as their association with standard prognostic factors and therapeutic response. PATIENTS AND METHODS: This case-control study included 60 pediatric patients newly diagnosed with B-ALL and 30 pediatric controls. The patient CD27 and CD44 levels were measured using the Beckman Coulter Navios Flow Cytometer. RESULTS: Most malignant cells (91.6 %) expressed CD44, but only 50 % of the patients had CD27 expressed. The positive CD 44 expression was associated with unfavorable prognostic markers, including a decrease.

Tailored Time-Temperature Transformation Diagram for IN718 Alloy Obtained via Powder Bed Fusion Additive Manufacturing: Phase Behavior and Precipitation Dynamic.

Experimental and computational approaches were used to study the microstructure of IN718 produced via powder bed fusion additive manufacturing (PBF-AM). The presence, chemical composition, and distribution of stable and metastable phases (γ'', δ, MC, and Laves) were also analyzed. The information obtained from the microstructural study was used to construct a tailored time-temperature transformation (TTT) diagram customized for additive manufacturing of IN718. Experimental techniques, including differential scanning calorimetry (DSC), scanning electron microscopy, energy dispersive X-ray spectroscopy, and electron backscatter diffraction (EBSD), were employed to establish the morphological, chemical, and structural characteristics of the microstructure. The Thermo-Calc software and a Scheil-Gulliver model were used to analyze the presence and behavior of phase transformations during heating and cooling processes under non-thermodynamic equilibrium conditions, typical of AM processes. Unlike conventional TTT diagrams of this alloy, the diagram presented here reveals that the precipitation of γ'' and δ phases occurs at lower temperatures and shorter times in AM-manufactured parts. Significantly, the superposition of γ'' and δ phase curves in the proposed diagram underscores the interdependence between these phases. This TTT diagram is a valuable insight that can help in the development of heat treatment processes and quality control for IN718 produced via PBF-AM.

Factores que intervienen en el desempeño de los estudiantes en las Pruebas de Estado Saber Pro / Factors Involved in Student Performance in the Saber Pro State Tests

Resumen: Las pruebas Saber Pro son evaluaciones estandarizadas que miden al estudiante con relación a su proceso formativo, pero en ocasiones se cree que los resultados solo se deben a asuntos académicos. Esta investigación busca identificar los fac tores que afectan el desempeño de las personas en las pruebas de Estado Saber Pro. La metodología empleada es cualitativa, la técnica para recoger informa ción fue la entrevista y la encuesta. Como conclusión se dice que, el estudiante se encuentra influenciado por múltiples escenarios como la familia, lo laboral, la situación económica y el barrio como escenarios próximos donde habita que interfieren en sus resultados de las pruebas.

Abstract: The Saber Pro tests are standardized evaluations that measure students in re lation to their educational process, but sometimes it is believed that the results are only due to academic issues. This research seeks to identify the factors that affect people's performance in the Saber Pro state tests. The methodology used is qualitative, the technique to collect information was the interview and the survey. As a conclusion, it is said that the student is influenced by multiple sce narios, such as family, work, economic situation and the neighborhood where they live, which interfere in their test results.

Primary standardization and Monte Carlo modeling of (243Am + 239Np) by means of a 4π(PC)-γ coincidence counting system.

The procedure followed by the Nuclear Metrology Laboratory (LMN) at the IPEN for the primary standardization of a (243Am + 239Np) solution, in secular equilibrium, is described. The measurement was carried out in a 4π(PC) (α,ß)-γ coincidence system. The total activity per unit mass of the solution was determined by the extrapolation technique, using a software coincidence counting systsem. The extrapolation curves were compared with Monte Carlo calculations by means of Code ESQUEMA, used in previous works, which, was improved and applied in order to calculate the alpha, beta, gamma, X-rays and coincidence spectra.

Cannabinoid CB2 receptor agonist reduces local and systemic inflammation associated with pneumonia-induced sepsis in mice.

Sepsis is a severe condition secondary to dysregulated host response to infection leading to tissue damage and organ dysfunction. Cannabinoid CB2 receptor has modulatory effects on the immune response. Therefore, this study investigated the effects of a cannabinoid CB2 receptor agonist on the local and systemic inflammatory process associated with pneumonia-induced sepsis. Pneumonia-induced sepsis was induced in mice by intratracheal inoculation of Klebsiella pneumoniae. Tissue and bronchoalveolar lavage (BAL) were collected 6, 24, or 48 h after surgery. Mice were treated with CB2 agonist (AM1241, 0.3 and 3 mg/kg, i.p.) and several parameters of inflammation were evaluated 24 h after sepsis induction. Polymorphonuclear cell migration to the infectious focus peaked 24 h after pneumonia-induced sepsis induction in male and female animals. Septic male mice presented a significant reduction of cannabinoid CB2 receptor density in the lung tissue after 24 h, which was not observed in females. CB2 expression in BAL macrophages was also reduced in septic animals. Treatment of septic mice with AM1241 reduced cell migration, local infection, myeloperoxidase activity, protein extravasation, and NOS-2 expression in the lungs. In addition, the treatment reduced plasma IL-1ß, increased IL-10 and reduced the severity and mortality of septic animals. These results suggest that AM1241 promotes an interesting balance in the inflammatory response, maintaining lung function and preventing organ injury. Therefore, cannabinoid CB2 receptors are potential targets to control the excessive inflammatory process that occurs in severe conditions, and agonists of these receptors can be considered promising adjuvants in pneumonia-induced sepsis treatment.

Anandamide reduces the migration of lymphocytes to the intestine by CB2 activation and reduces TNF-α in the target organs, protecting mice from graft-versus-host disease.

Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.

Toxicity of Synthetic Cannabinoids in K2/Spice: A Systematic Review.

(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as 'K2', 'K9' or 'Spice'. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings.

Arbuscular Mycorrhizal Fungi Promote Physiological and Biochemical Advantages in Handroanthus serratifolius Seedlings Submitted to Different Water Deficits.

Climate change causes increasingly longer periods of drought, often causing the death of plants, especially when they are in the early stages of development. Studying the benefits provided by arbuscular mycorrhizal (AM) fungi to plants in different water regimes is an efficient and sustainable strategy to face climate change. Thus, this study investigated the influence of AM fungi on Handroanthus serratifolius seedlings under different water regimes, based on biochemical, and nutritional growth parameters. The experiment was carried out in H. serratifolius seedlings cultivated with mycorrhizas (+AMF) and without mycorrhizas (-AMF) in three water regimes; a severe water deficit (SD), a moderate water deficit (MD), and a well-watered (WW) condition. AM fungi provided greater osmoregulation under water deficit conditions through the accumulation of soluble sugars, total free amino acids, and proline, as well as by reducing sugar. The increase in the absorption of phosphorus and nitrate was observed only in the presence of fungi in the well-watered regimen. A higher percentage of colonization was found in plants submitted to the well-watered regimen. Ultimately, AM fungi promoted biochemical, nutritional, and growth benefits for H. serratifolius seedlings under the water deficit and well-hydrated conditions, proving that AMF can be used to increase the tolerance of H. serratifolius plants, and help them to survive climate change.

Temporal trends in the epidemiology of inflammatory bowel diseases in the public healthcare system in Brazil: A large population-based study.

Background: Population-based data on epidemiology of Inflammatory Bowel Diseases (IBD) in Brazil are scarce. This study aims to define temporal trends of incidence and prevalence rates of Crohn's disease (CD) and ulcerative colitis (UC) in Brazil. Methods: All IBD patients from the public healthcare national system were included from January 2012 to December 2020. Average Annual Percent Change (AAPC) and 95% confidence intervals (CI) were calculated using log-linear regression for incidence and binomial regression for prevalence. Moran's I autocorrelation index was used to analyse clustering of cities by level of prevalence. Findings: A total of 212,026 IBD patients were included. Incidence of IBD rose from 9.4 in 2012 to 9.6 per 100,000 in 2020 (AAPC=0.8%; 95% CI -0.37, 1.99); for UC, incidence increased from 5.7 to 6.9 per 100,000 (AAPC=3.0%; 95% CI 1.51, 4.58) and for CD incidence decreased from 3.7 to 2.7 per 100,000 (AAPC=-3.2%; 95% CI -4.45, -2.02). Prevalence of IBD increased from 30.0 in 2012 to 100.1 per 100,000 in 2020 (AAPC=14.8%; CI 14.78-14.95); for UC, from 15.7 to 56.5 per 100,000 (AAPC=16.0%; CI 15.94, 16.17); for CD from 12.6 to 33.7 per 100,000 (AAPC=12.1% CI 11.95, 12.02). A south-north gradient was observed in 2020 prevalence rates of IBD [I=0.40 (p<0.0001)], CD [I=0.22 (p<0.0001)] and UC [I=0.42 (p<0.0001)]. Interpretation: Incidence of CD is decreasing whereas of UC is increasing, leading to stabilization in the incidence of IBD from 2012 to 2020 in Brazil. Prevalence of IBD has been climbing with 0.1% of Brazilians living with IBD in 2020. Funding: None.

Smart Spectrophotometric Methods for Concurrent Determination of Furosemide and Spironolactone Mixture in Their Pharmaceutical Dosage Forms

Abstract Simple, precise, accurate and specific spectrophotometric methods are progressed and validated for concurrent analysis of Furosemide (FUR) and Spironolactone (SPR) in their combined dosage form depend on spectral analysis procedures. Furosemide (FUR) in the binary mixture could be analyzed at its λmax 274 nm using its recovered zero order absorption spectrum using constant multiplication method (CM). Spironolactone (SPR) in the mixture could be analyzed at its λmax 238 nm by ratio subtraction method (RS). Concurrent determination for FUR and SPR in their mixture could be applied by amplitude modulation method (AM), absorbance subtraction method (AS) and ratio difference (RD). Linearity ranges of FUR and SPR were (2.0µg/mL-22.0 µg/mL) and (3.0µg/mL-30.0 µg/mL), respectively. Specificity of the proposed spectrophotometric methods was examined by analyzing the prepared mixtures in laboratory and was applied successfully for pharmaceutical dosage form analysis which have the cited drugs without additives contribution. The proposed spectrophotometric methods were also validated as per as the guidelines of ICH. Statistical comparison was performed between the obtained results with those from the official methods of the cited drugs, using one-way ANOVA, F-test and student t-test. The results are exhibiting insignificant difference concerning precision and accuracy

Biogeographic Patterns of Arbuscular Mycorrhizal Fungal Communities Along a Land-Use Intensification Gradient in the Subtropical Atlantic Forest Biome.

Information concerning arbuscular mycorrhizal (AM) fungal geographical distribution in tropical and subtropical soils from the Atlantic Forest (a global hotspot of biodiversity) are scarce and often restricted to the evaluation of richness and abundance of AM fungal species at specific ecosystems or local landscapes. In this study, we hypothesized that AM fungal diversity and community composition in subtropical soils would display fundamental differences in their geographical patterns, shaped by spatial distance and land-use change, at local and regional scales. AM fungal community composition was examined by spore-based taxonomic analysis, using soil trap cultures. Acaulospora koskei and Glomus were found as generalists, regardless of mesoregions and land uses. Other Acaulospora species were also found generalists within mesoregions. Land-use change and intensification did not influence AM fungal composition, partially rejecting our first hypothesis. We then calculated the distance-decay of similarities among pairs of AM fungal communities and the distance-decay relationship within and over mesoregions. We also performed the Mantel test and redundancy analysis to discriminate the main environmental drivers of AM fungal diversity and composition turnover. Overall, we found significant distance-decays for all land uses. We also observed a distance-decay relationship within the mesoregion scale (< 104 km) and these changes were correlated mainly to soil type (not land use), with the secondary influence of both total organic carbon and clay contents. AM fungal species distribution presented significant distance-decays, regardless of land uses, which was indicative of dispersal limitation, a stochastic neutral process. Although, we found evidence that, coupled with dispersal limitation, niche differentiation also played a role in structuring AM fungal communities, driven by long-term historical contingencies, as represented by soil type, resulting from different soil origin and mineralogy across mesoregions.

Oportunidades de estimulação motora em ambientes domiciliares do Amazonas e fatores associados / Opportunities for motor stimulation in home environments of Amazonas and associated factors / Oportunidades de estimulación motora en ambientes domiciliarios de Amazonas y factores asociados

O objetivo do presente estudo foi analisar as oportunidades de estimulação motora em ambientes domiciliares e fatores associados em crianças de Parintins/Amazonas. Participaram 300 pais/responsáveis por crianças da cidade de Parintins/Amazonas. Affordances in the Home Environment for Motor Development foi utilizado para avaliar oportunidades de estimulação motora. A prevalência de baixa estimulação moto-ra foi 78% maior nas casas em que moravam quatro ou mais adultos (RP: 1,78; IC95%: 1,07-2,87); mães com o ensino fundamental (RP: 15,93; IC95%:2,45-17,50) e ensino médio (RP: 10,07; IC95%: 1,46-54,01) forne-cem baixa estimulação motora; e crianças do sexo masculino apresenta-ram maior probabilidade de baixa estimulação motora (RP: 1,56; IC95%: 1,09-1,94). Identificamos que lares nessa região não ofertam oportuni-dades de estimulação motora adequada para as crianças.

The objective was to analyze the opportunities for motor stimulation of home environments and associated factors in children from Parintins/Amazonas. Participants included 300 parents/guardians of children from the city of Parintins/ Amazonas participated. Affordances in the Home Environment for Motor Development was used to assess opportunities for motor stimulation. The prevalence of low motor stimulation was 78% higher in the homes where four or more adults lived (PR: 1.78; 95% CI: 1.07-2.87); mothers with elementary school (PR: 15.93; 95% CI: 2.45-17.50) and high school (PR: 10.07; 95% CI: 1.46-54.01) provide low motor stimulation; and male children were more likely to have low motor stimulation (PR: 1.56; 95% CI: 1.09-1.94). We identified that homes in this region do not offer opportunities for adequate motor stimulation for children.

El objetivo fue analizar las oportunidades de estimulación motora de los ambientes domésticos y factores asociados en niños de Parintins/Amazonas. Los participantes incluyeron a 300 padres/tutores de niños de la ciudad de Parintins/Amazonas. Se utilizó Affordances in the Home Environment for Motor Development para evaluar las oportunidades de estimulación motora. La prevalencia de estimulación motora baja fue 78% mayor en los hogares donde vivían cuatro o más adultos (RP: 1,78; IC 95%: 1,07-2,87); las madres con escuela primaria (RP: 15,93; IC del 95%: 2,45-17,50) y secundaria (RP: 10,07; IC del 95%: 1,46-54,01) proporcionan una estimulación motora baja; y los niños varones tenían más probabilidades de tener una estimulación motora baja (PR: 1,56; IC del 95%: 1,09-1,94). Identificamos que los hogares en esta región no ofrecen oportunidades para la estimulación motora adecuada para los niños.

Cannabidiol induces antidepressant and anxiolytic-like effects in experimental type-1 diabetic animals by multiple sites of action.

Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists - 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.

URB597 Prevents the Short-Term Excitotoxic Cell Damage in Rat Cortical Slices: Role of Cannabinoid 1 Receptors.

Endocannabinoid-based therapies constitute an emerging tool for the potential treatment of neurodegenerative disorders, requiring characterization at the experimental level. The effects of URB597, an inhibitor of the fatty acid amide hydrolase (FAAH), were tested against the quinolinic acid (QUIN)-induced early toxic effects in rat cortical slices, and compared with those effects exerted by the endocannabinoid anandamide (AEA). URB597 prevented the QUIN-induced loss of mitochondrial function/cell viability and lipid peroxidation, while reduced necrosis, and to a lesser extent, apoptosis. The protective effects of URB597 were mediated by activation of cannabinoid receptor 1 (CB1r), as evidenced by their inhibition by the selective CB1r antagonist AM281. Similar effects were observed when testing AEA against QUIN toxicity. Our findings demonstrate the neuroprotective properties of URB597 during the early stages of excitotoxic damage to cortical tissue, suggesting that these properties are mediated by FAAH inhibition, and might be linked to the protective effects of AEA, or the combination of endocannabinoids.

The PKC-ζ pseudosubstrate peptide induces glutamate release from retinal pigment epithelium cells through kinase- independent activation of Best1.

AIMS: The retinal pigment epithelium (RPE) is a highly specialized cell monolayer, that plays a key role in the maintenance of photoreceptor function and the blood-retina barrier (BRB). In this study, we found that a myristoylated pseudosubstrate of PKC-ζ (PKCζ PS), considered as a PKC-ζ inhibitor, plays a distinct role in RPE. MAIN METHODS: We demonstrated that PKCζ PS stimulates the release of Glutamate (Glu) using in vitro3H-Glutamate release experiments. By western blot, kinase assays, and Fluoresence Ca+2 Concentration Measurements, we determined the cellular mechanisms involved in such release. KEY FINDINGS: Surprisingly, PKCζ PS has no effect on either phosphorylation of T560, essential for catalytic activity, nor it has an effect on kinase activity. It induces the dose-dependent release of Glu by increasing intracellular Ca+2 levels. Interestingly, this release was not observed upon stimulation by other non-competitive PKC-ζ inhibitors. We here demonstrated that the PKCζ PS stimulates the release of Glutamate from RPE by activating the Ca2+-dependent Cl channel Bestrophin 1 (Best1). SIGNIFICANCE: These results question PKCζ PS specificity as an inhibitor of this enzyme. Furthermore, the present results underline the relevance of clarifying the molecular mechanisms involved in glutamate release from the retina under conditions derived from excitotoxic stimuli.