Birthweight and its association with cardiometabolic risk parameters in rural Maya children from Yucatan, Mexico.

BACKGROUND: Knowledge about the influence of early developmental factors on cardiometabolic health in the Maya is limited. AIM: To analyse the relationship between birthweight (BW) and cardiometabolic parameters in a sample of rural Maya children from Yucatan, Mexico. SUBJECTS AND METHODS: We took anthropometric measurements and obtained data on BW and fasting blood samples in a sample of 75 children aged 5-14 years. Dependent variables were: fat mass index (FMI), body mass index (BMI), glucose (G), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), LDL/HDL and TC/HDL ratios and metabolic index (TGxG/HDL2). Outcomes were transformed to y = 100 log(e)x and the resulting estimates are interpreted as symmetrical percentage differences. The main independent variable was BW z-score. Multiple linear regression analyses were used to assess the relationship between BW and outcomes. RESULTS: An increase of one standard deviation in BW predicted 6.6% (95% CI [-11.6, -1.6]) decrease in HDL and 11% (95% CI [3.7, 18.4]), 7.8% (95% CI [2.3, 13.2]) and 19.6% (95% CI [3.1, 36]) increases in LDL/HDL, TC/HDL and metabolic index, respectively. CONCLUSION: Higher birthweights were associated with adverse levels of biochemical parameters in this sample of rural Maya children.

Secular trends in the anthropometric characteristics of children in a rural community in Yucatan, Mexico.

OBJECTIVE: To analyze changes in height, weight, and body mass index (BMI = kg/m2 ) from 1986 to 2022 in 3-11 year old children from Dzeal, a rural Maya community in Yucatan, Mexico. MATERIALS AND METHODS: From October-2022 to February-2023 (third-wave survey), we obtained anthropometric measurements of children (n = 80) and family socioeconomic data and compared them with data obtained in 1986 (n = 38) and 2000 (n = 76). Comparisons of anthropometric parameters by sex between years of measurement were performed graphically and through one-way ANOVA, splitting children into two age groups: 3-7 and 8-11. Bonferroni adjustments for multiple comparisons were used when ANOVAs were statistically significant (p < .05). RESULTS: In girls, significant increases in height and weight between surveys were found in 3-7 and 8-11 age groups; in boys, significant increases were only found in the 8-11 age group. Regarding BMI, there were increases in 2022 compared with 1986/2000 in both sexes from 8 years onwards. Differences indicate increases of 3.9 and 4.4 cm per decade in girls aged 3-7 and 8-11, respectively, and increases in weight of 1.1 and 3.3 kg per decade, respectively. Increases in boys 8-11 years were 2.3 cm and 2.4 kg per decade. CONCLUSION: Significant increases in growth parameters were observed in specific-age children in the community studied in the context of changes in livelihoods and improvements in household material conditions.

Effect and mechanisms of resveratrol in animal models of ischemic stroke: A systematic review and Bayesian meta-analysis.

Resveratrol (RSV) holds promise as cerebroprotective treatment in cerebral ischemia. This systematic review aims to assess the effects and mechanisms of RSV in animal models of ischemic stroke. We searched Medline, Embase and Web of Science to identify 75 and 57 eligible rodent studies for qualitative and quantitative syntheses, respectively. Range of evidence met 10 of 13 STAIR criteria. Median (Q1, Q3) quality score was 7 (5, 8) on the CAMARADES 15-item checklist. Bayesian meta-analysis showed SMD estimates (95% CI) favoring RSV: infarct size (-1.72 [-2.03; -1.41]), edema size (-1.61 [-2.24; -0.98]), BBB impairment (-1.85 [-2.54; -1.19]), neurofunctional impairment (-1.60 [-1.92; -1.29]), and motor performance (1.39 [0.64; 2.08]); and less probably neuronal survival (0.63 [-1.40; 2.48]) and apoptosis (-0.96 [-2.87; 1.02]). Species (rat vs mouse) was associated to a larger benefit. Sensitivity analyses confirmed robustness of the estimates. Reduction of oxidative stress, inflammation, and apoptosis underlie these effects. Our results quantitatively state the beneficial effects of RSV on structural and functional outcomes in rodent stroke models, update the evidence on the mechanisms of action, and provide an exhaustive list of targeted signaling pathways. Current evidence highlights the need for conducting further high-quality preclinical research to better inform clinical research.

Cerebroprotective Effect of 17ß-Estradiol Replacement Therapy in Ovariectomy-Induced Post-Menopausal Rats Subjected to Ischemic Stroke: Role of MAPK/ERK1/2 Pathway and PI3K-Independent Akt Activation.

Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17ß-estradiol (E2) is neuroprotective against stroke in both male and female rodents. However, the molecular mechanisms by which E2 intervenes in ischemia-induced cell death, revealing these sex differences, remain unclear. The present study was aimed to determine, in female rats, the molecular mechanisms of two well-known pro-survival signaling pathways, MAPK/ERK1/2 and PI3K/Akt, that mediate E2 neuroprotection in response to acute ischemic stroke. E2 pretreatment reduced brain damage and attenuated apoptotic cell death in ovariectomized female rats after an ischemic insult. Moreover, E2 decreased phosphorylation of ERK1/2 and prevented ischemia/reperfusion-induced dephosphorylation of both Akt and the pro-apoptotic protein, BAD. However, MAPK/ERK1/2 inhibitor PD98059, but not the PI3K inhibitor LY294002, attenuated E2 neuroprotection. Thus, these results suggested that E2 pretreatment in ovariectomized female rats modulates MAPK/ERK1/2 and activates Akt independently of PI3K to promote cerebroprotection in ischemic stroke. A better understanding of the mechanisms and the influence of E2 in the female sex paves the way for the design of future successful hormone replacement therapies.

Brain Cell Senescence: A New Therapeutic Target for the Acute Treatment of Ischemic Stroke.

Aging is a major risk factor for cerebral infarction. Since cellular senescence is intrinsic to aging, we postulated that stroke-induced cellular senescence might contribute to neural dysfunction. Adult male Wistar rats underwent 60-minute middle cerebral artery occlusion and were grouped according to 3 reperfusion times: 24 hours, 3, and 7 days. The major biomarkers of senescence: 1) accumulation of the lysosomal pigment, lipofuscin; 2) expression of the cell cycle arrest markers p21, p53, and p16INK4a; and 3) expression of the senescence-associated secretory phenotype cytokines interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-1ß (IL-1ß) were investigated in brain samples. Lipofuscin accumulation was scarce at the initial stage of brain damage (24 hours), but progressively increased until it reached massive distribution at 7 days post-ischemia. Lipofuscin granules (aggresomes) were mainly confined to the infarcted areas, that is parietal cortex and adjacent caudate-putamen, which were equally affected. The expression of p21, p53, and p16INK4a, and that of IL-6, TNF-α, and IL-1ß, was significantly higher in the ischemic hemisphere than in the non-ischemic hemisphere. These data indicate that brain cell senescence develops during acute ischemic infarction and suggest that the acute treatment of ischemic stroke might be enhanced using senolytic drugs.

The Associations Between Maternal Socioeconomic Factors and Adequacy of Energy and Macronutrient Intakes in Pregnant Women From Yucatan, Mexico.

BACKGROUND: Socioeconomic factors influence diet quality during pregnancy. However, a dearth of evidence about the influence on energy and macronutrients adequacy calls for research. OBJECTIVE: To analyze the association between socioeconomic factors and adequacy rates of energy and macronutrient intakes in pregnant women from Merida, Yucatan, Mexico. METHODS: During September to December 2019, we applied a socioeconomic questionnaire and three 24-hour dietary recalls to 83 pregnant females resident in Merida, Yucatan. Energy and macronutrient intakes were compared with the estimated trimester-specific energy and macronutrient requirements to calculate adequacies (%). Outcome variables were average adequacy of energy, carbohydrates, total fat, and protein intakes and the main predictors were maternal education, monthly family income, working status, and marital status. Descriptive statistics of adequacy were calculated for each category of predictors. The association between socioeconomic factors and outcome variables was analyzed through simple and multiple linear regression models. RESULTS: Adequacy rates of energy and macronutrients decreased as education and familial income levels increased, as well as among unemployed women. Consistently with these results, simple linear regressions showed that years of education, family income, and working status (i.e., women working to earn money), were negatively associated with adequacy rates of energy and macronutrients intakes. When all predictors and covariates were included in a multiple linear regression model, only having a job was significantly associated with adequacy rates. Marital status was not associated with outcomes. CONCLUSIONS: Women in disadvantaged socioeconomic conditions (unemployed and low levels of education and familial income) show greater energy and macronutrient intakes.

Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline.

Prolinamides are well-known organocatalysts for the HSiCl3 reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)-N-(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the N-pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl3-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process.

Chiral Imidazolium Prolinate Salts as Efficient Synzymatic Organocatalysts for the Asymmetric Aldol Reaction.

Chiral imidazolium l-prolinate salts, providing a complex network of supramolecular interaction in a chiral environment, have been studied as synzymatic catalytic systems. They are demonstrated to be green and efficient chiral organocatalysts for direct asymmetric aldol reactions at room temperature. The corresponding aldol products were obtained with moderate to good enantioselectivities. The influence of the presence of chirality in both the imidazolium cation and the prolinate anion on the transfer of chirality from the organocatalyst to the aldol product has been studied. Moreover, interesting match/mismatch situations have been observed regarding configuration of chirality of the two components through the analysis of results for organocatalysts derived from both enantiomers of prolinate (R/S) and the trans/cis isomers for the chiral fragment of the cation. This is associated with differences in the corresponding reaction rates but also to the different tendencies for the formation of aggregates, as evidenced by nonlinear effects studies (NLE). Excellent activities, selectivities, and enantioselectivities could be achieved by an appropriate selection of the structural elements at the cation and anion.

The Role of NF-κB Triggered Inflammation in Cerebral Ischemia.

Cerebral ischemia is a devastating disease that affects many people worldwide every year. The neurodegenerative damage as a consequence of oxygen and energy deprivation, to date, has no known effective treatment. The ischemic insult is followed by an inflammatory response that involves a complex interaction between inflammatory cells and molecules which play a role in the progression towards cell death. However, there is presently a matter of controversy over whether inflammation could either be involved in brain damage or be a necessary part of brain repair. The inflammatory response is triggered by inflammasomes, key multiprotein complexes that promote secretion of pro-inflammatory cytokines. An early event in post-ischemic brain tissue is the release of certain molecules and reactive oxygen species (ROS) from injured neurons which induce the expression of the nuclear factor-kappaB (NF-κB), a transcription factor involved in the activation of the inflammasome. There are conflicting observations related to the role of NF-κB. While some observe that NF-κB plays a damaging role, others suggest it to be neuroprotective in the context of cerebral ischemia, indicating the need for additional investigation. Here we discuss the dual role of the major inflammatory signaling pathways and provide a review of the latest research aiming to clarify the relationship between NF-κB mediated inflammation and neuronal death in cerebral ischemia.

Insight into the molecular sex dimorphism of ischaemic stroke in rat cerebral cortex: Focus on neuroglobin, sex steroids and autophagy.

Including sex is of paramount importance in preclinical and clinical stroke researches, and molecular studies dealing in depth with sex differences in stroke pathophysiology are needed. To gain insight into the molecular sex dimorphism of ischaemic stroke in rat cerebral cortex, male and female adult rats were subjected to transient middle cerebral artery occlusion. The expression of neuroglobin (Ngb) and other functionally related molecules involved in sex steroid signalling (oestrogen and androgen receptors), steroidogenesis (StAR, TSPO and aromatase) and autophagic activity (LC3B-II/LC3B-I ratio, UCP2 and HIF-1α) was assessed in the ipsilateral ischaemic and contralateral non-ischaemic hemispheres. An increased expression of Ngb was detected in the injured female cerebral cortex. In contrast, increased expression of oestrogen receptor α, GPER, StAR, TSPO and UCP2, and decreased androgen receptor expression were detected in the injured male cortex. In both sexes, the ischaemic insult induced an upregulation of LC3B-II/-I ratio, indicative of increased autophagy. Therefore, the cerebral cortex activates both sex-specific and common molecular responses with neuroprotective potential after ischaemia-reperfusion, which globally results in similar stroke outcome in both sexes. Nonetheless, these different potential molecular targets should be taken into account when neuroprotective drugs aiming to reduce brain damage in ischaemic stroke are investigated.

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17ß-oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway.

Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg-1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60 minutes) and assigned to one of three groups treated with either: vehicle, BZA (3 mg kg-1  day-1 , i.p.) or 17ß-oestradiol (E2 ) (100 µg kg-1  day-1 , i.p.). At 24 hours post-ischaemia-reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)α, ERß and G protein-coupled oestrogen receptor), and activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3-kinase/Akt pathways were analysed. At 24 hours after the ischaemic insult, both BZA- and E2 -treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death. Ischaemia-reperfusion induced a significant decrease in ERα and ERß expression without affecting that of G protein-coupled oestrogen receptor, whereas BZA and E2 reversed such a decrease. The ischaemic insult up-regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3-kinase/Akt pathways; BZA and E2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion.

[MASK (Mobile Airways Sentinel Network). ARIA's comprehensive solution for mobile app for the multimorbidity of allergic rhinitis and asthma]. / MASK (Mobile Airways Sentinel Network). La solución integral de ARIA por app móvil para la multimorbilidad de rinitis alérgica y asma.

The vast majority of patients with allergic rhinitis (AR) do not receive the proper management which is recommended by the guidelines, but they frequently self-medicate. MASK (Mobile Airways Sentinel Network) is an integral part of a project that is supported by the European Union against chronic diseases and focused on active and healthy aging. MASK represents the third phase of ARIA (Allergic Rhinitis and its Impact on Asthma), in which, by using a mobile application in a smart device, the objective is to guide the patient in the control of his/her multi-morbidity, AR and/or allergic conjunctivitis (AC) and/or asthma. The mobile app Allergy Diary by MACVIA-ARIA is free and it is available for both Android and iOS platforms. After it is downloaded to the patient's cell phone, it first requests some information about the patient's profile, allergic pathologies and medication; afterwards, through a visual analog scale, the patient is invited to determine the degree of affectation in the nose, eyes, and bronchi, and its influence on their productivity at work / school. After analyzing the data generated by filling the Allergy Diary, it became clear there is a new clinical entity: allergic rhinitis+ allergic conjunctivitis +asthma, with greater effect; in addition to a high level of self-medication: in general, the patient takes medication on days when symptoms are present. The app has already been deployed in 23 countries, including several Spanish-speaking countries.

La mayoría de los pacientes con rinitis alérgica no recibe el manejo idóneo, sino que se automedica. MASK (Mobile Airways Sentinel Network) forma parte integral de un proyecto apoyado por la Unión Europea contra las enfermedades crónicas y enfocado al envejecimiento activo y saludable. Constituye la tercera fase de ARIA (Allergic Rhinitis and its Impact on Asthma), en la cual mediante una aplicación móvil en un dispositivo inteligente se intenta guiar al paciente en el control de su multimorbilidad, rinitis o conjuntivitis alérgicas o asma. La aplicación Diario de Alergia por MACVIA-ARIA es gratuita y está disponible para Android e iOS. Al descargarla al celular del paciente, a este se le piden datos de su perfil, patologías alérgicas y medicación; posteriormente, mediante una escala visual analógica se le invita a determinar el grado de afectación en nariz, ojos y bronquios y su influencia sobre su productividad laboral/escolar. Con los datos del Diario de Alergia se observa que existe un nuevo patrón de presentación: rinitis alérgica + conjuntivitis alérgica + asma, con mayor afectación, así como un alto nivel de automedicación: en general, el paciente toma medicación cuando presenta síntomas. La app se ha desplegado en 23 países, incluyendo varios países hispanohablantes.

Potassium channels contribute to the increased sensitivity of the rabbit carotid artery to hydrogen sulfide in diabetes.

Hydrogen sulfide (H2S) is a potential endothelium-derived hyperpolarizing factor (EDHF) and adventitium- or adipocyte-derived relaxing factor (ADRF) which vasorelaxant action is mediated by potassium channels. H2S could also play an important role in the pathophysiology of diabetic cardiovascular complications. The present study has investigated the influence of alloxan-induced diabetes on the role of potassium channels mediating the relaxant response of the rabbit carotid artery to NaHS, a donor of H2S. NaHS (10-8-3 × 10-5 M) relaxed phenylephrine-precontracted carotid arteries, with higher potency in diabetic than in control rabbits. The selective blockers of potassium channels charybdotoxin, 4-amynopiridine and glibenclamide significantly inhibited the relaxant action of NaHS in diabetic rabbits, but not in control rabbits. When compared to control rabbits, carotid arteries from diabetic rabbits showed significantly reduced expression of big conductance Ca+2-activated potassium channels (BKCa), significantly enhanced expression of intermediate conductance Ca+2-activated potassium channels (IKCa) and not significant different expression of voltage-sensitive potassium channels (KV) and ATP-sensitive potassium channels (KATP). These results suggest that an enhanced role of IKCa, KV and KATP potassium channels could be involved in the increased sensitivity of the rabbit carotid artery to H2S in diabetes.

Divergent Multistep Continuous Synthetic Transformations of Allylic Alcohol Enabled by Catalysts Immobilized in Ionic Liquid Phases.

Two individual catalytic platforms (metal- and organo-catalyzed) based on the use of an ionic liquid phase were successfully integrated for the synthesis of α-cyano-amine and cyanohydrin trimethylsilyl ethers from allylic alcohol. The right combination of continuous flow processes enabled access to the divergent preparation of two alternative and interesting intermediate compounds from the same starting material.

Emergent Uric Acid Treatment is Synergistic with Mechanical Recanalization in Improving Stroke Outcomes in Male and Female Rats.

Preclinical and clinical studies support a promising, albeit not definitive, neuroprotective effect of emergent uric acid (UA) administration in ischemic stroke. We assessed the effects of UA in an ischemic stroke model relevant to the current treatment paradigm of mechanical thrombectomy within the STAIR/RIGOR recommendations. A cohort of male and female Wistar rats was subjected to ischemic stroke with mechanical recanalization under physiological monitoring. The effects of transient middle cerebral artery occlusion (tMCAO) with adjunctive UA (IV, 16 mg/kg) or vehicle treatment were assessed at 24 h and 7 days. Outcomes included neurofunctional impairment, brain infarct (TTC staining, MRI imaging and cresyl violet staining) and edema. At 24 h after tMCAO, neurofunctional scores and brain infarct were significantly reduced in rats subjected to UA treatment compared to vehicle, with a selective effect of UA on cortical infarct. No differential effect of UA between male and female rats was evidenced, as no significant interaction of sex with stroke outcomes was found. Rats achieving higher reperfusion levels after tMCAO showed superior reduction of neurofunctional impairment, cortical infarct and edema by UA. After a 7-day follow-up, male rats subjected to UA treatment still showed reductions in neurofunctional impairment and infarct size, compared to vehicle treatment. In conclusion, UA treatment immediately after transient ischemia results in a sex-independent, maintained reduction of brain damage and neurological impairment, better manifested in hyperperfusion conditions. This synergistic effect of UA with mechanical recanalization supports additional clinical testing of UA as an adjunctive treatment to mechanical thrombectomy.

Molecular mechanisms underlying the neuroprotective role of atrial natriuretic peptide in experimental acute ischemic stroke.

Along with its role in regulating blood pressure and fluid homeostasis, the natriuretic peptide system could be also part of an endogenous protective mechanism against brain damage. We aimed to assess the possibility that exogenous atrial natriuretic peptide (ANP) could protect against acute ischemic stroke, as well as the molecular mechanisms involved. Three groups of rats subjected to transient middle cerebral artery occlusion (tMCAO, intraluminal filament technique, 60 min) received intracerebroventricular vehicle, low-dose ANP (0.5 nmol) or high-dose ANP (2.5 nmol), at 30 min reperfusion. Neurofunctional condition, and brain infarct and edema volumes were measured at 24 h after tMCAO. Apoptotic cell death and expression of natriuretic peptide receptors (NPR-A and NPR-C), K+ channels (KATP, KV and BKCa), and PI3K/Akt and MAPK/ERK1/2 signaling pathways were analyzed. Significant improvement in neurofunctional status, associated to reduction in infarct and edema volumes, was shown in the high-dose ANP group. As to the molecular mechanisms analyzed, high-dose ANP: 1) reduced caspase-3-mediated apoptosis; 2) did not modify the expression of NPR-A and NPR-C, which had been downregulated by the ischemic insult; 3) induced a significant reversion of ischemia-downregulated KATP channel expression; and 4) induced a significant reversion of ischemia-upregulated pERK2/ERK2 expression ratio. In conclusion, ANP exerts a significant protective role in terms of both improvement of neurofunctional status and reduction in infarct volume. Modulation of ANP on some molecular mechanisms involved in ischemia-induced apoptotic cell death (KATP channels and MAPK/ERK1/2 signaling pathway) could account, at least in part, for its beneficial effect. Therefore, ANP should be considered as a potential adjunctive neuroprotective agent improving stroke outcome after successful reperfusion interventions.

Is Participatory Action Research an innovative pedagogical alternative for training teachers as researchers? The training plan and evaluation for normal schools.

Normal schools in Mexico train teachers for basic level education. Classified as Higher Education Institutions, part of their mandate is to conduct scientific research to improve educational quality. Currently, normal school students can meet graduation requirements by either writing a thesis or reporting on professional practice using Participatory Action Research (PAR). Teachers at normal schools have only limited experience in conducting and supervising PAR projects. With the aim of analyzing the situation and addressing this paradox, we used PAR to develop a plan to train normal school teachers in application of PAR methodology. We present the training proposal and evaluate its results in a pilot phase. These suggest that PAR represents an innovative option for training teachers to conduct research and therefore fulfill part of their responsibilities at normal schools in Mexico. Changes in institutional culture and structure would be required for successful implementation of PAR in this context.

Diabetes modifies the role of prostanoids and potassium channels which regulate the hypereactivity of the rabbit renal artery to BNP.

Diabetic nephropathy is associated with increased risk of cardiovascular disease. B-type natriuretic peptide (BNP) plays an important role in cardiovascular pathophysiology and therapeutics. The aim of the present study was to investigate the influence of experimental diabetes on the mechanisms that regulate the relaxant response of the rabbit renal artery to BNP. Arterial relaxations to BNP were enhanced in diabetic rabbits. Indomethacin enhanced BNP-induced relaxation in control rabbits but showed no effect in diabetic rabbits. BNP-induced release of thromboxane A2 or prostacyclin was not different in both groups of animals. Iberiotoxin had no effect on relaxations to BNP in both groups of animals. Charybdotoxin displaced to the right the concentration-response curve to BNP in both group of animals, and inhibited BNP-induced relaxation only in diabetic rabbits. Glibenclamide did not modify the BNP-induced relaxations in control rabbits, but inhibited it in diabetic rabbits. These results suggest that diabetes induces hypereactivity of the rabbit renal artery to BNP by mechanisms that at least include (1) a reduced vasoconstrictor influence of arachidonic acid metabolites via cyclooxygenase 2, which is not related with changes in thromboxane A2 and prostacyclin release from the arterial wall and (2) a selectively increased modulatory activity of KATP and endothelial IKCa channels.

The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia.

Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the apoptotic cell death. In this context, p53 is a stress sensor that accumulates during brain ischemia leading to neuronal death. The murine double minute 2 gene (MDM2), a p53-specific E3 ubiquitin ligase, is the main cellular antagonist of p53, mediating its degradation by the proteasome. Here, we study the role of MDM2-p53 pathway on PC-induced neuroprotection both in cultured neurons (in vitro) and rat brain (in vivo). Our results show that PC increased neuronal MDM2 protein levels, which prevented ischemia-induced p53 stabilization and neuronal death. Indeed, PC attenuated ischemia-induced activation of the p53/PUMA/caspase-3 signaling pathway. Pharmacological inhibition of MDM2-p53 interaction in neurons abrogated PC-induced neuroprotection against ischemia. Finally, the relevance of the MDM2-p53 pathway was confirmed in rat brain using a PC model in vivo. These findings demonstrate the key role of the MDM2-p53 pathway in PC-induced neuroprotection against a subsequent ischemic insult and poses MDM2 as an essential target in ischemic tolerance.