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Introduction: Plant growth-promoting rhizobacteria (PGPR) can increase plant growth and encapsulation of PGPR with biochar ensures the viability and survival of PGPR. However, this approach is still underexplored. Objectives: The objectives of this study: 1) to isolate and select a potential PGPR from rice rhizosphere based on plant growth-promoting characterization, 2) encapsulate the selected PGPR strain SA-10 using biochar and sodium alginate, and 3) assess the effect of encapsulated and non-encapsulated SA-10 on chili plant growth compared to a non-inoculated SA-10 and control. Methodology: SA-10 was isolated from rice rhizosphere and characterized for plant growth promoting traits including, the nitrogen fixation, phosphate solubilization, production of siderophore, production of indole acetic acid and production of cellulose degradation enzyme. SA-10 was encapsulated in alginate beads along with biochar. A pot experiment conducted using encapsulated SA-10, non-encapsulated SA-10, and a control group to assess the effects of encapsulated SA-10 application on chili plants using complete randomized design (CRD) experimental design with four replications. Results: About 28 bacteria isolates were isolated from the rhizosphere and endospheric of rice crops to determine their effects on the growth of chili plants. The isolates were characterized with zinc, phosphate, and potassium solubilization, siderophores production, and cellulose degradation. The findings showed isolate SA-10 solubilized zinc at a rate of 41.6 %, phosphate at 50 %, and potassium at 76.9 %. It also fixed nitrogen, produced siderophores and degraded cellulose. The isolate also produced the highest IAA at 4.007 mg/L. Isolate SA-10 was then encapsulated in a mixture of biochar and sodium alginate. The results showed that plants treated with encapsulated SA-10 had significantly higher leaf area (3.68 cm2), leaf diameter (6.55 cm), and dry weight (0.39 g) compared to those treated with non-encapsulated and the control treatment. Through 16S rRNA gene sequencing, it was identified that SA-10 belongs to the Enterobacter genus, closely resembling Enterobacter chuandaensis. Conclusion: The findings suggest that Enterobacter sp. SA-10 enhances plant growth, and the use of encapsulated SA-10 with biochar contributes to the growth of chili plants. The encapsulated Enterobacter sp. SA-10 has a promising potential in enhancing crop yield production and promoting sustainable agriculture.

The high-performance demands on industrial floors, both in terms of larger slab dimensions and increased durability under harsh operating conditions, have led to the growing use of expansive admixtures. These generate a controlled expansive reaction within the concrete and compensate the early-age shrinkage. Despite their increasing use, calculation methods that permit to consider the expansive agents during the pavement design phase with a certain level of reliability are still unexistent. This study presents a straightforward cross-sectional model to assess both the stress-strain state and joint-opening of concrete pavements with volumetric stability admixtures by considering the slab dimensions, concrete composition, exposure conditions, and base friction characteristics. For that, a novel experimental device is designed and implemented in this work to characterize the dimensional variations associated with expansive agents since casting. A Type-G commercial volumetric stability admixture is considered as the expansive admixture. A full-scale validation of the proposed model is performed on a jointless concrete panel constructed by RCR Industrial Flooring in Spain. This validation proves the feasibility of the combined approach of laboratory calibration of the expansive addition and the cross-sectional model presented to accurately estimate both the slab deformations and joint opening developed over the 77-day test period.

TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.

The article presents the general characteristics and peculiarities of the legal regulation of public procurement within the European Union. Public procurement is extremely important both for European integration and for states as a whole due to the fact that it is a significant sector of the economy. To date, the issue of legal regulation of public procurement is relevant throughout the world, and the direct subject is the state itself, which is interested in their maximum efficiency. The purpose of the authors is to conduct a legal analysis of the EU Directives, as well as international treaties to which this integration association is a party, establishing common standards and norms in the field of regulation of public pro-curement. While carrying out this research the authors used such general scientific methods as method of scientific abstraction, qualitative expert assessment, quantitative assessment and structural analysis. The theoretical significance of the study consist of the fact that the work provides theoretical conclusions that can be used in scientific and practical developments on the problematic issues raised. In conclusion, the authors notes the effectiveness of the European system of organization of public procurement, imple-mented on the basis of its principles and approaches, which make it possible to form effective national systems of public procurement, corresponding to the world standards.

Abstract Background Iron deficiency (ID) and anemia are common in both heart failure (HF) and cancer patients and are associated with poor quality of life and survival. The aims of this study were (1) to evaluate the prevalence, types, and confounding factors of ID and anemia in patients referred to cardio-oncology clinic, and (2) identify the association between iron metabolism parameters and survival of cardio-oncology patients. Methods We assessed iron, ferritin, hemoglobin concentrations, transferrin saturation (TSAT), cancer type, brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), kidney function, cardiovascular risk factors and survival in 599 patients who were referred to cardio-oncology clinic from 2011 to 2017. ID was defined by a TSAT

The article presents a General description of the regulation of public procurement by the UNCITRAL Model law on public procurement in 2011 as a tool for interstate integration in this area. Today, the issue of legal regulation of public procurement is relevant all over the world, and the direct subject is the state itself, which is interested in the maximum efficiency of this process. The aim of the authors is to analyze the above-mentioned document, which establishes common standards and norms in the field of regulation of public procurement. This paper presents a comparative analysis of the 1994 UNCITRAL Model law on procurement of goods, construction and services and the 2011 UNCITRAL Model law on public procurement. This article emphasizes the legal and economic significance of public procurement. The authors ‘ conclusions are based on the work of foreign scientists and experts from international organizations. In conducting this study, the authors used such General scientific methods and techniques as the method of comparative analysis, scientific abstraction, qualitative expert assessments, quantitative assessments, and structural analysis. In their conclusions, the authors note that effective achievement of public procurement objectives can only be achieved through interrelated and consistent procedures based on the basic principles and conditions contained in the 2011 UNCITRAL Model law on public procurement. Key words: UNCITRAL, public procurement, efficiency, transparency, model law.

In this paper, we propose a method based on applying specific transformations to the Global Navigation Satellite System (GNSS) signals received in unfavorable environment. As a result, one simple classical receiver including these adjustments becomes sensitive to several Multi-Constellation and Multi-Frequency (MC/MF) GNSS signals and achieves efficiently their collective acquisition. The proposed method consists of three variants each dedicated to a particular type of Binary Offset Carrier (BOC) family signals; the primary is based on undersampling process, the second is founded on time expansion and the last one permits the acquisition of more than five different GNSS signals by a single local Composite Binary Coded Symbols (CBCS) waveform replica. Hence, the proposed scheme, by avoiding the use of multiple demodulators in the baseband, allows less receiver complexity and accordingly better realization cost. The simulation results showed that the proposed method presents an effective solution for the reception of MC/MF signals in unfavorable environments.

There has been a significant growth in the elderly population of developing countries. This growth leads health systems in those countries to face an increase in consultations for oral diseases for this age group. Therefore, the biopsychosocial approach is essential for healthy aging in the elderly. The objectives of this review article are to identify the psychological factors that have a relationship with most prevalent oral diseases in elderly people (dental caries and periodontal disease), and then describe how tooth loss, the principal consequence of caries and periodontal disease, impacts the mental health of older people. Finally, some proposals for dental work in the elderly are discussed, considering the psychological factors related to oral health.

Для понимания политической и правовой системы Казахстана большое значение имеет знание исторических основ и динамики тех процессов, которые происходят в стране. С целью достижения этой цели важно применение исторического и сравнительного методов исследования. Только на их основе можно строить определенные прогнозы в отношении будущего страны, его политической и правовой системы. Авторы рассматривают истоки политической и правовой системы Казахстана с точки зрения истории и современности, уделяя особое внимание применяемым дефинициям. Так, в рамках изучения истоков политической системы Казахстана особое внимание уделяется понятию политической системы общества, существующим в этой сфере теориям, а также типологии политических систем. Авторы подчеркивают особую роль государства, являющегося центральным элементом политической системы общества. В статье рассмотрена история политической системы Казахстана, начиная с момента создания Казахского ханства, возникшего на обломках Золотой Орды, заканчивая советским периодом и особенностями политической системы современного Казахстана. Специфика современной политической системы Казахстана заключается в ведущей роли государства, оказывающего решающее влияние на политическую систему страны. При рассмотрении правовой системы Казахстана основной упор был сделан на разграничение понятий «правовая система», «система права» и «система законодательства». При этом авторы исходят из того, как понимаются эти термины в Казахстане и других постсоветских государствах. Обращение к истории формирования правовой системы Казахстана начинается с эпохи Казахского ханства (XV век), после чего авторы останавливаются на особенностях права казахов в составе Российской империи и Советского Союза. В конце данного раздела анализируются особенности правовой системы современного Казахстана. Авторы формулируют вывод о том, что правовая система, построенная в Казахстане и в России, является однотипной, что отвечает внешнеполитическому курсу Казахстана, нацеленному на тесную интеграцию постсоветских государств и являющемуся одной из главных его внешних функций. Ключевые слова: Казахстан, политическая система, правовая система, истоки, функции государства.

Here we present the results of 3D computer modeling of combustion coal-dust in the combustion chamber of the boiler BKZ-75. Calculations performed by the numerical model for the conditions adopted by the organization of the actual process on Shahtynskaya Thermal Power Plant. Carried out in this paper, the research allowed identifying the main patterns of distribution of heat exchange performance in the entire volume of the combustion chamber of the researched boiler and at the exit from it. The authors carried out numerical experiments of 3D computer modeling for describing complex processes of heat and mass transfer. Proposed the numerical methods of solving a system of equations describing heat and mass transfer, and a program package has been developed for solving combustion problems. New computer modeling results of turbulent heat-and mass transfer process received during burning coal-dust fuel in the combustion chamber of the BKZ-75 boiler. The developed technologies will make it possible to exclude inefficient and costly methods of conducting research in the field of fuel-burning energy industry. Numerical modeling including thermodynamic, kinetic and three-dimensional computer modeling of burning low-grade Kazakhstan coal will optimize the process of ignition, combustion and stabilization of coal combustion, and also develop technical solutions for the modernization of existing power plants and for the design of new power boilers.

In this paper deals with development and application the numerical model for solution of processes at combustion chamber of the industrial boiler. The combustion chamber of the BKZ-75 boiler installed at Shakhtinskaya Thermal Power Plant (Karaganda, Kazakhstan) was chosen as the object of the research. As a result of computational experiments obtained distribution of concentrations of harmful substances: CO2, CO, NO throughout the volume of the combustion chamber and on an output from it. In addition, the authors received a distribution of oxygen depending on the height of the combustion chamber. The minimum and maximum values of the investigated characteristics are established. The dynamics of the change in the characteristics of the heat and mass exchange process in the volume of the researched combustion chamber is shown. Obtained results give quantitative information on the amount of combustion products including harmful substances. The numerical model becomes a tool for investigation and design of combustion chambers with high-efficiency and reliable operation of boiler at thermal power plants. The results of this research has high practical importance, they allow studying heat exchange processes occurring in combustion in real geometry areas (combustion chambers of power plants).

The article analyzes the practice of the WTO dispute resolution body and cases, which were considered even under the GATT for anti-dumping cases. The result of the analysis is systematization and determination of the general characteristics of the precedents of the above topics, as well as the definition of innovation in the new dispute resolution procedure. To put it more clearly, it should be emphasized that the procedure for settling trade disputes of the WTO Dispute Resolution Body is not entirely new, but has been in effect since the establishment of the organization, but because of article considers precedents that preceded the WTO disputes, there was an objective need to make a comparative analysis between the two procedures on the resolution of trade disputes. The authors distinguish two main innovations, which, in turn, consist of two elements and are mainly expressed in institutional and operational new introductions. Undoubtedly, such a reform of the procedure has a positive effect and increases the effectiveness of measures, which makes the WTO dispute resolution body a more attractive institution for parties to trade disputes. The features of the anti-dumping precedents are based on the specifics of the dispute resolution procedure, which is subject to the norms of the code, developed taking into account the complexities of disputes, the object of which is dumping. Therefore, in determining the general characteristics, the main categories were the stages of the dispute and already in stages, tendencies were derived. Key words: anti-dumping, GATT, WTO, WTO innovations.

The present work describes the results of a study of structuring ability of water-soluble polymers such as polydimethyl diallyl ammonium chloride, saponification product of polyacrylonitrile (uniflok) and their interpolymer complex. On the kinetics of growth of Rehbinder’s plastic durability of coagulation structure of soil concentrated suspensions the effect of water soluble polymers and interpolymer complexes on the structure formation in the dispersions was studied. It was determined that the process is a two-step process which was caused by the adsorption step process: the binding of macromolecules with the soil surface by the random segments and conformational changes of macromolecules in the adsorbed layer. It was found that the soil stability structured by polymers against wind and water erosion increased with the concentration of water-soluble polymers. This is due to the increase of the structure formation in concentrated suspensions of soil in the presence of water soluble polymers. On the basis of the results it can be concluded that the treatment of mineral dispersions by water-soluble polymers alone or in the form of the interpolymer complex leads to a significant reduction of dust-and run-off of soil particles. The PDMDAAC/uniflok interpolymer complex in comparison with polymers reduces intensively the deflation which has a great economic and ecological importance.

Objetivo. Describir las características sociodemográficas y las determinantes de la utilización de los servicios de salud por la población de 60 años y más en México. Material y métodos. De la información captada en la Encuesta Nacional de Salud II se obtuvieron datos de 4 628 personas ancianas; se analizaron las prevalencias de las principales enfermedades crónicas y en los individuos que utilizaron los servicios de salud dos semanas antes de la encuesta se investigaron los factores determinantes de su utilización. Resultados. Las enfermedades crónicas más frecuentemente notificadas fueron: hipertensión arterial, diabetes mellitus y cardiopatías. La tasa de utilización de servicios en ese grupo de edad fue de 11.4%, y de hospitalización 5.5%. Los servicios de salud más utilizados fueron: el médico particular, el Instituto Mexicano del Seguro Social (IMSS), la Secretaría de Salud, el Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado y el IMSS-Solidaridad. De 25 a 45% de los derechohabientes no hacen uso de estos servicios y, en su lugar, acuden a los servicios privados. Las variables explicativas más importantes de la utilización de servicios fueron: el estar enfermo, no haber trabajado la semana anterior y ser derechohabiente. El género, la zona de residencia y el grado de escolaridad no fueron significativos en la explicación de la utilización de servicios de salud. Conclusiones. El estudio demuestra la necesidad de fortalecer los programas preventivos y de apoyo para esta población, ya que sólo acude a los servicios de salud cuando está enferma.Objective. To describe the sociodemographic characteristics and determinants of health services utilization by the Mexican population of 60 years of age or more. Materials and methods. Information obtained from the National Health Survey II (ENSA-II) allowed analysis of 4 628 elderly people. Prevalence of chronic diseases was analyzed and the determinants of individuals who had used the health services in the two weeks prior to the interview. Results. The chronic diseases most frequently reported were: hypertension, diabetes and heart disease. The utilization and hospitalization rates of that age group were 11.4 and 5.5%, respectively. The services most frequently used were: the private physician, social security (IMSS, ISSSTE) welfare services (Ministry of Health SSA and IMSS-Solidaridad). Interestingly, 25 to 45% of social security insurance holders did not use the services, instead they consulted a private physician. The most important explanatory variables for health services utilization were: the perceived illness, not having worked for the previous week and being a social security insurance holder. Gender, area of residence and level of education were not significant in the explanation of health services utilization. Conclusions. This study demonstrates the need to strengthen preventive and support programs for the elderly population, since they only demand health services when they feel sick.

Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+) T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Several epidemiological and preclinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β-amyloid (Aβ) production and inhibit neuroinflammation. However, follow-up clinical trials, mostly using selective cyclooxygenase (COX)-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX-1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro-inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX-1 inhibition, rather than COX-2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20-month-old triple transgenic AD (3 × Tg-AD) mice with the COX-1 selective inhibitor SC-560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC-560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg-AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX-1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg-AD mice. Thus, selective COX-1 inhibition should be further investigated as a potential therapeutic approach for AD., (Published 2012. This article is a US Government work and is in the public domain in the USA.)

Like macrophages, microglia are functionally polarized into different phenotypic activation states, referred as classical and alternative. The balance of the two phenotypes may be critical to ensure proper brain homeostasis, and may be altered in brain pathological states, such as Alzheimer's disease. We investigated the role of NADPH oxidase in microglial activation state using p47(phox) and gp91(phox) -deficient mice as well as apocynin, a NADPH oxidase inhibitor during neuroinflammation induced by an intracerebroventricular injection of LPS or Aβ₁₋₄₂. We showed that NADPH oxidase plays a critical role in the modulation of microglial phenotype and subsequent inflammatory response. We demonstrated that inhibition of NADPH oxidase or gene deletion of its functional p47(phox) subunit switched microglial activation from a classical to an alternative state in response to an inflammatory challenge. Moreover, we showed a shift in redox state towards an oxidized milieu and that subpopulations of microglia retain their detrimental phenotype in Alzheimer's disease brains. Microglia can change their activation phenotype depending on NADPH oxidase-dependent redox state of microenvironment. Inhibition of NADPH oxidase represents a promising neuroprotective approach to reduce oxidative stress and modulate microglial phenotype towards an alternative state., (Published 2011. This article is a US Government work and is in the public domain in the USA.)

Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Cyclooxygenase (COX)-derived prostaglandins promote the migration of several immune cells in vitro, however, the specific roles of COX-1 and -2 on leukocyte recruitment in vivo have not been investigated. To examine the specific effects of COX-1 or COX-2 deficiency on neuroinflammation-induced leukocyte infiltration, we used a model of intracerebroventricular lipopolysaccharide (LPS)-induced neuroinflammation in COX-1(-/-), COX-2(-/-), and their respective wild-type (WT) ((+/+)) mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1(-/-) and increased in COX-2(-/-) mice, compared with their respective WT controls. This influx of leukocytes was accompanied by a marked disruption of blood-brain barrier and differential expression of chemokines. These results indicate that COX-1 and COX-2 deletion differentially modulate leukocyte recruitment during neuroinflammation, and suggest that inhibition of COX-1 activity is beneficial, whereas COX-2 inhibition is detrimental, during a primary neuroinflammatory response.

Background: Passive immunization with antibodies directed to Aβ decreases brain Aβ/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD). This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema)., Methods: We intravenously administered the monoclonal Aβ protofibril antibody PFA1 to aged (22 month) male and female 3 × tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum Aβ and CNS cytokine levels. We also examined 17 month old 3 × tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization., Results: The 22 month old male mice immunized with PFA1 had decreased brain Aβ, increased serum Aβ, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain Aβ, decreased serum Aβ, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 × tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain Aβ and increased serum Aβ accompanied by a decrease in CNS MCP-1., Conclusions: These data suggest that passive immunization with PFA1 in 3 × tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain Aβ. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines.

Neuroinflammation is a critical component in the progression of several neurological and neurodegenerative diseases and cyclooxygenases (COX)-1 and -2 are key regulators of innate immune responses. We recently demonstrated that COX-1 deletion attenuates, whereas COX-2 deletion enhances, the neuroinflammatory response, blood-brain barrier permeability and leukocyte recruitment during lipopolysaccharide (LPS)-induced innate immune activation. Here, we used transgenic mice, which overexpressed human COX-2 via neuron-specific Thy-1 promoter (TgCOX-2), causing elevated prostaglandins (PGs) levels. We tested whether neuronal COX-2 overexpression affects the glial response to a single intracerebroventricular injection of LPS, which produces a robust neuroinflammatory reaction. Relative to non-transgenic controls (NTg), 7 month-old TgCOX-2 did not show any basal neuroinflammation, as assessed by gene expression of markers of inflammation and oxidative stress, neuronal damage, as assessed by Fluoro-JadeB staining, or systemic inflammation, as assessed by plasma levels of IL-1beta and corticosterone. Twenty-four hours after LPS injection, all mice showed increased microglial activation, as indicated by Iba1 immunostaining, neuronal damage, mRNA expression of cytokines (TNF-alpha, IL-6), reactive oxygen expressing enzymes (iNOS and NADPH oxidase subunits), endogenous COX-2, cPLA(2) and mPGES-1, and hippocampal and cortical IL-1beta levels. However, the increases were similar in TgCOX-2 and NTg. In NTg, LPS increased brain PGE(2) to the levels observed in TgCOX-2. These results suggest that PGs derived from neuronal COX-2 do not play a role in the neuroinflammatory response to acute activation of brain innate immunity. This is likely due to the direct effect of LPS on glial rather than neuronal cells., (Published by Elsevier Ireland Ltd.)

Cyclooxygenases (COX) -1 and -2 are key regulators of innate immune responses. We recently demonstrated that the expression of proinflammatory cytokines and chemokines is reduced in COX-1 null ((-/-)), and increased in COX-2(-/-) mice compared with their respective wild type controls during lipopolysaccharide (LPS)-induced innate immune activation. As chemokines are involved in leukocyte recruitment into the inflamed brain, we hypothesized that COX-1 and COX-2 deletion will differentially modulate blood-brain barrier (BBB) permeability in response to LPS. In the present study, using quantitative magnetic resonance imaging, we found that LPS-induced BBB disruption was exacerbated in COX-2(-/-) versus COX-2(+/+) mice. In the hippocampus and cortex of LPS-treated mice, matrix metalloproteinase (MMP)-3 activity was significantly decreased in COX-1(-/-) mice, whereas in COX-2(-/-) mice the activity of both MMP-9 and MMP-3, known to mediate BBB breakdown, was increased. Brain mRNA expression of the leukocyte attracting chemokine Cxcl10, the intercellular interaction molecule Icam-1, the pan-leukocyte marker Cd45 was increased in COX-2(-/-) versus COX-2(+/+) mice, whereas Cxcl10 and Cd45 mRNA expression was decreased in COX-1(-/-) versus COX-1(+/+) mice after LPS. Altogether, these results indicate that COX-2 activity modulates MMP-9 and-3 activities and is necessary to maintain BBB integrity during toll-like receptor 4-dependent innate immune activation.

Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component.

Background: Cyclooxygenases (COX) -1 and -2 are key mediators of the inflammatory response in the central nervous system. Since COX-2 is inducible by inflammatory stimuli, it has been traditionally considered as the most appropriate target for anti-inflammatory drugs. However, the specific roles of COX-1 and COX-2 in modulating a neuroinflammatory response are unclear. Recently, we demonstrated that COX-1 deficient mice show decreased neuroinflammatory response and neuronal damage in response to lipopolysaccharide (LPS)., Methods: In this study, we investigated the role of COX-2 in the neuroinflammatory response to intracerebroventricular-injected LPS (5 mug), a model of direct activation of innate immunity, using COX-2 deficient (COX-2-/-) and wild type (COX-2+/+) mice, as well as COX-2+/+ mice pretreated for 6 weeks with celecoxib, a COX-2 selective inhibitor., Results: Twenty-four hours after LPS injection, COX-2-/- mice showed increased neuronal damage, glial cell activation, mRNA and protein expression of markers of inflammation and oxidative stress, such as cytokines, chemokines, iNOS and NADPH oxidase. Brain protein levels of IL-1beta, NADPH oxidase subunit p67phox, and phosphorylated-signal transducer and activator of transcription 3 (STAT3) were higher in COX-2-/- and in celecoxib-treated mice, compared to COX-2+/+ mice. The increased neuroinflammatory response in COX-2-/- mice was likely mediated by the upregulation of STAT3 and suppressor of cytokine signaling 3 (SOCS3)., Conclusion: These results show that inhibiting COX-2 activity can exacerbate the inflammatory response to LPS, possibly by increasing glial cells activation and upregulating the STAT3 and SOCS3 pathways in the brain.