Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples.

Diagnosis of nutritional status, dyslipidemia and associated risk factors in indigenous Yaqui schoolchildren.

BACKGROUND: Malnutrition is a global problem that affects schoolchildren and can increase the risk of diseases in adulthood. Adult members of the Yaqui Indigenous group have been shown to have serious health problems, and Yaqui schoolchildren could therefore find themselves in a similar situation. OBJECTIVE: To evaluate the nutritional status, lipid profile and associated factors in a sample of Yaqui schoolchildren. MATERIAL AND METHODS: A total of 109 Yaqui schoolchildren who lived in their localities of origin were recruited. Anthropometric measurements were carried out, a venous blood sample was extracted in fasting conditions, and several questionnaires were applied. RESULTS: The prevalence of overweight/obesity was 38.5%, with no cases of chronic malnutrition being recorded; 38.6% of the children had dyslipidemia. Fiber consumption was a protective factor against overweight/obesity, while fat intake was a risk factor. The physical activity score was found to be a protective factor against dyslipidemia, and the risk factors were BMI-for-age Z-scores, waist circumference, family history of dyslipidemia, educational level, and permanent employment. CONCLUSIONS: Yaqui schoolchildren equally suffer from a high proportion of overweight/obesity and dyslipidemia. The associated factors may be useful for the design of contextualized interventions for this population.

ANTECEDENTES: La malnutrición es un problema mundial que afecta a niños escolares, capaz de incrementar el riesgo de enfermedades en la edad adulta. Adultos yaquis han presentado graves problemas de salud, por lo que los escolares podrían encontrarse en una situación similar. OBJETIVO: Evaluar el estado nutricional, el perfil lipídico y los factores asociados en una muestra de escolares yaquis. MATERIAL Y MÉTODOS: Se estudiaron 109 escolares habitantes de los pueblos originarios, en quienes se realizaron mediciones antropométricas, se extrajo una muestra de sangre venosa en condición de ayuno y se aplicaron cuestionarios. RESULTADOS: La prevalencia de sobrepeso/obesidad fue de 38.5 %, sin que se registraran casos de desnutrición crónica; 38.6 % de los escolares presentó dislipidemia. El consumo de fibra resultó ser un factor protector contra sobrepeso/obesidad y el consumo de grasa constituyó un factor de riesgo. La puntuación de actividad física resultó ser un factor protector contra dislipidemia y los factores de riesgo fueron puntuaciones Z del índice de masa corporal/edad, circunferencia de cintura, historia familiar de dislipidemias, nivel educativo y empleo permanente. CONCLUSIONES: Los escolares yaquis padecen por igual alta proporción de sobrepeso/obesidad y dislipidemia. Los factores asociados pueden resultar útiles para el diseño de intervenciones contextualizadas para esta población.

Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease.

The alteration of the endocannabinoid tone usually associates with changes in the expression and/or function of the cannabinoid CB1 receptor. In Alzheimer's disease (AD), amyloid beta (Aß)-containing aggregates induce a chronic inflammatory response leading to reactivity of both microglia and astrocytes. However, how this glial response impacts on the glial CB1 receptor expression in the subiculum of a mouse model of AD, a brain region particularly affected by large accumulation of plaques and concomitant subcellular changes in microglia and astrocytes, is unknown. The CB1 receptor localization in both glial cells was investigated in the subiculum of male 5xFAD/CB2 EGFP/f/f (AD model) and CB2 EGFP/f/f mice by immuno-electron microscopy. The findings revealed that glial CB1 receptors suffer remarkable changes in the AD mouse. Thus, CB1 receptor expression increases in reactive microglia in 5xFAD/CB2 EGFP/f/f , but remains constant in astrocytes with CB1 receptor labeling rising proportionally to the perimeter of the reactive astrocytes. Not least, the CB1 receptor localization in microglial processes in the subiculum of controls and closely surrounding amyloid plaques and dystrophic neurites of the AD model, supports previous suggestions of the presence of the CB1 receptor in microglia. These findings on the correlation between glial reactivity and the CB1 receptor expression in microglial cells and astrocytes, contribute to the understanding of the role of the endocannabinoid system in the pathophysiology of Alzheimer's disease.

Signaling through the type 2 cannabinoid receptor regulates the severity of acute and chronic graft-versus-host disease.

Graft-versus-host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R), which is expressed on nearly all immune cells, and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells or administration of a selective CB2R pharmacological antagonist exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells, indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T-cell alloreactivity. Using a novel CB2ReGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists Δ9-tetrahydrocannabinol (THC) and JWH-133 revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contributed to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and extracellular regulated kinase phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. This study shows that the CB2R plays a critical role in the regulation of GVHD and suggests that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of anti-retroviral toxic neuropathy.

Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 - ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretroviral agent Zalcitabine (2',3'-dideoxycytidine; ddC). We also used a conditional knockout approach to identify cell types mediating CB2 agonist-induced antinociceptive efficacy and sparing of morphine tolerance. AM1710 and LY2828360 alleviated ddC-induced neuropathic nociception in mice of both sexes. These benefits were absent in global CB2 knockout mice, which exhibited robust morphine antinociception. Like morphine, AM1710 blunted ddC-induced increases in proinflammatory cytokine (IL-1ß, TNF-α) and chemokine (CCL2) mRNA expression levels. We generated advillinCre/+;CB2f/f conditional knockout mice to ascertain the role of CB2 localized to primary sensory neurons in CB2-mediated therapeutic effects. Antinociceptive efficacy of both AM1710 and LY2828360, but not reference analgesics, were absent in advillinCre/+;CB2f/f mice, which exhibited robust ddC-induced neuropathy. In ddC-treated CB2f/f mice, LY2828360 suppressed development of morphine tolerance and reversed established morphine tolerance, albeit with greater efficacy in male compared to female mice. LY2828360 failed to block or reverse morphine tolerance in advillinCre/+;CB2f/f mice. The present studies indicate that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.

Determination of Fat-Free Mass Density and its Components in Older Hispanic Adults by In Vivo Methods.

The densitometry method estimates body composition based on cadaver reference values, mainly the fat-free mass density value of 1.100 g/cm3. However, several changes in fat-free mass components by aging, ethnicity, and excess adiposity could influence their density and affect body composition estimations. The present study aimed to compare the mean fat-free mass component values in older Hispanic adults to cadaver reference values. This cross-sectional study included a sample of 420 subjects aged ≥60 yr from northern Mexico. Fat-free mass was determined by the four-compartment model using air displacement plethysmography, the deuterium dilution technique, and dual-energy X-ray absorptiometry for body density, aqueous and mineral fractions of body weight, respectively. A 1-sample t test was used to compare the fat-free mass density and aqueous, mineral, and residue fractions of fat-free mass from subjects in the study to the assumed cadaver reference values. The mean fat-free mass density value for the total sample of older Hispanic adults (1.096 ± 0.011 g/cm3) was significantly (p < 0.001) lower than the assumed value of 1.100 g/cm3, except in obese older men. The mean aqueous fraction of fat-free mass (74.8 ± 3.3%) was higher than the assumed value of 73.8%, and the mean residue fraction of fat-free mass value was lower (18.3 ± 3.4%) than the reference value of 19.4%. Indeed, only the mean mineral fraction of fat-free mass value (6.8 ± 0.8%) was similar to the reference value. In the total sample, all characteristic mean fat-free mass values in these older Hispanic adults differed from cadaver reference values, except the mineral fraction of fat-free mass value.

Prevalence of overweight, obesity and central obesity and factors associated with BMI in indigenous yaqui people: a probabilistic cross-sectional survey.

BACKGROUND: The Yaquis are an Indigenous group who inhabit in the state of Sonora in northwestern Mexico. This group has experienced changes in their lifestyle, moving from a traditional lifestyle to a more modern one, resulting in an increase of obesity and its comorbidities. However, few studies have been done in this group. The aim of this study was to determine the prevalence of overweight, obesity and central obesity and to identify the factors associated with body mass index (BMI) in a representative sample of Indigenous Yaqui people from Sonora, Mexico. METHODS: A cross-sectional survey with multistage sampling was conducted among adults (N = 351) with residence in Yaqui traditional villages (Vícam, Pótam, Loma de Guamúchil, Loma de Bácum, Tórim, Ráhum, Huiribis or Belem). Anthropometric measurements were taken to diagnose overweight, obesity and central obesity. Food frequency and physical activity (PA) questionnaires designed for the Yaqui population were applied, as well as sociodemographic and clinical history questionnaires. The factors associated with BMI were assessed using multiple linear regression considering the complex design of the sampling. RESULTS: The prevalence of overweight, obesity and central obesity in the population were 36.5%, 35.0% and 76.0%, respectively. Having higher values of the modernization index (ß = 0.20, p = 0.049) was associated with a higher BMI, while having a higher consumption of a "prudent" dietary pattern (traditional dishes, fruits, vegetables and low-fat dairy) (ß = -0.58, p = 0.009) and performing a greater number of hours per week of vigorous PA (ß = -0.14, p = 0.017) were associated with a lower BMI. CONCLUSIONS: The prevalence of the studied abnormalities is high. The evidence presented in this study suggests that interventions are needed and more research is required to determine the appropriate components of such interventions, in order to meet the needs of the Yaqui people.

Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer's disease.

BACKGROUND: The complex pathophysiology of Alzheimer's disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. METHODS: In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse- model. RESULTS: We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3-CA1 synapse, both basal synaptic transmission and long-term potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron-glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH-/- animals. CONCLUSION: In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer's disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the disease.

Development of High-Specificity Fluorescent Probes to Enable Cannabinoid Type 2 Receptor Studies in Living Cells.

Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous conditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this receptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism of CB2R signaling, especially in cell-type and tissue-dependent contexts. Herein, we report for the first time a versatile ligand platform for the modular design of a collection of highly specific CB2R fluorescent probes, used successfully across applications, species, and cell types. These include flow cytometry of endogenously expressing cells, real-time confocal microscopy of mouse splenocytes and human macrophages, as well as FRET-based kinetic and equilibrium binding assays. High CB2R specificity was demonstrated by competition experiments in living cells expressing CB2R at native levels. The probes were effectively applied to FACS analysis of microglial cells derived from a mouse model relevant to Alzheimer's disease.

Cannabinoid CB2R receptors are upregulated with corneal injury and regulate the course of corneal wound healing.

CB2R receptors have demonstrated beneficial effects in wound healing in several models. We therefore investigated a potential role of CB2R receptors in corneal wound healing. We examined the functional contribution of CB2R receptors to the course of wound closure in an in vivo murine model. We additionally examined corneal expression of CB2R receptors in mouse and the consequences of their activation on cellular signaling, migration and proliferation in cultured bovine corneal epithelial cells (CECs). Using a novel mouse model, we provide evidence that corneal injury increases CB2R receptor expression in cornea. The CB2R agonist JWH133 induces chemorepulsion in cultured bovine CECs but does not alter CEC proliferation. The signaling profile of CB2R activation is activating MAPK and increasing cAMP accumulation, the latter perhaps due to Gs-coupling. Lipidomic analysis in bovine cornea shows a rise in acylethanolamines including the endocannabinoid anandamide 1 h after injury. In vivo, CB2R deletion and pharmacological block result in a delayed course of wound closure. In summary, we find evidence that CB2R receptor promoter activity is increased by corneal injury and that these receptors are required for the normal course of wound closure, possibly via chemorepulsion.

Effect of multi-component school-based program on body mass index, cardiovascular and diabetes risks in a multi-ethnic study.

BACKGROUND: Mexico occupies one of the first places worldwide in childhood obesity. Its Mestizo and Indigenous communities present different levels of westernization which have triggered different epidemiological diseases. We assessed the effects of a multi-component school-based intervention program on obesity, cardiovascular and diabetes risk factors. METHODS: A physical activity, health education and parent involvement (PAHEPI) program was developed and applied in six urban (Mestizo ethnic group) and indigenous (Seri and Yaqui ethnic groups) primary schools for 12 weeks. A total of 320 children aged 4-12 years participated in intervention program; 203 under Treatment 1 (PAHEPI program) and 117, only from Mestizo groups, under Treatment 2 (PAHEPI+ school meals). For Body Mass Index (BMI), cardiovascular and diabetes factors, pairwise comparisons of values at baseline and after treatments were done using Wilcoxon signed rank test. Generalized linear models were applied to assess the intervention effect by age, sex and nutritional status in relation to ethnicity and treatment. RESULTS: We observed improvements on BMI in children with overweight-obesity and in triglycerides in the three ethnic groups. The Mestizo ethnic group showed the largest improvements under Treatment 2. While Seris showed improvements only in cardiovascular risk factors, Yaquis also showed improvements in diabetes risk factors, though not in BMI. CONCLUSIONS: This study showed that the same intervention may have positive but different effects in different ethnic groups depending on their lifestyle and their emerging epidemiological disease. Including this type of intervention as part of the school curriculum would allow to adapt to ethnic group in order to contribute more efficiently to child welfare. TRIAL REGISTRATION: This study was retrospectively registered under the identifier NCT03768245 .

[Moderate exercise and intake of either high or low glycemic index carbohydrates in sedentary women]. / Ejercicio moderado y consumo de alimentos de alto y bajo índice glucémico en mujeres sedentarias.

OBJECTIVE: To analyze changes in blood glucose, insulin and triglyceride concentrations in relation to a moderate aerobic exercise in sedentary women of different body weight, exposed to either a high or low glycemic index carbohydrates diet. DISEñO: Cross-over type. SITE: Research was performed in the Exercise Physiology Laboratory at Facultad de Ciencias de la Cultura Física, Universidad Autónoma de Chihuahua, México. PARTICIPANTS: Twenty-six young sedentary women who did not exercise in the last year participated in the study. Four of adequate weight (AW) and 2 with obesity (OB) were excluded for not consuming the suggested carbohydrates (1gr/kg of weight) nor completed the programed exercise. There were n=10 in each group (AW/OB). INTERVENTION: Two treatments of 55minutes of aerobic exercise each were applied one day after consuming either high or low glycemic index carbohydrates. MAIN MEASUREMENTS: Plasmatic glucose, insulin, and triglycerides were determined before and after the scheduled exercise. RESULTS: Glucose, insulin, and triglycerides were higher in OB than in AW at baseline. Glucose was normalized in OB from 5.8±0.35 to 5.3±0.23 mmol/L (P=.001), only by eating foods with low glycemic index; triglycerides increased from 139.5±66.0 to 150.8±67.2mg/dl (P=.004) at the end of the exercise, after consumption of low glycemic index carbohydrates. CONCLUSION: Elevation of triglycerides secondary to exercise after consumption of low glycemic index seems to indicate an increase of lipid oxidation in OB.

Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA.

Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome-wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; ß = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10-11 ), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10-9 ); genetic distances at HLA were greater than at random markers (P = 1.6 × 10-46 ). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10-10 ). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.

Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer's disease.

BACKGROUND: Because of their low levels of expression and the inadequacy of current research tools, CB2 cannabinoid receptors (CB2R) have been difficult to study, particularly in the brain. This receptor is especially relevant in the context of neuroinflammation, so novel tools are needed to unveil its pathophysiological role(s). METHODS: We have generated a transgenic mouse model in which the expression of enhanced green fluorescent protein (EGFP) is under the control of the cnr2 gene promoter through the insertion of an Internal Ribosomal Entry Site followed by the EGFP coding region immediately 3' of the cnr2 gene and crossed these mice with mice expressing five familial Alzheimer's disease (AD) mutations (5xFAD). RESULTS: Expression of EGFP in control mice was below the level of detection in all regions of the central nervous system (CNS) that we examined. CB2R-dependent-EGFP expression was detected in the CNS of 3-month-old AD mice in areas of intense inflammation and amyloid deposition; expression was coincident with the appearance of plaques in the cortex, hippocampus, brain stem, and thalamus. The expression of EGFP increased as a function of plaque formation and subsequent microgliosis and was restricted to microglial cells located in close proximity to neuritic plaques. AD mice with CB2R deletion exhibited decreased neuritic plaques with no changes in IL1ß expression. CONCLUSIONS: Using a novel reporter mouse line, we found no evidence for CB2R expression in the healthy CNS but clear up-regulation in the context of amyloid-triggered neuroinflammation. Data from CB2R null mice indicate that they play a complex role in the response to plaque formation.

Prevalence of prediabetes and modifiable factors in an ethnic group of Mexico: the Comcáac Project.

OBJECTIVE: To determine the prevalence of and modifiable factors associated with prediabetes in the Comcáac Indians. DESIGN: Cross-sectional study where prediabetes was defined using fasting plasma glucose, 2 h plasma glucose and glycated Hb (HbA1c). Physical, anthropometric and biochemical measurements, medical record, socio-economic, dietary and physical activity information were collected. The modifiable factors associated with prediabetes were assessed using multiple logistic regression. Settings Comcáac Indian communities of Punta Chueca and El Desemboque, Sonora, Mexico. SUBJECTS: Adults (n 227) aged 20 years or older. RESULTS: The sex- and age-adjusted prevalence (95 % CI) of prediabetes was 47·1 (40·8, 53·5) % in the overall population; age-adjusted prevalence was 47·3 (35·6, 59·0) % in men and 46·7 (39·1, 54·3) % in women. The modifiable factors associated with a risk of prediabetes (OR; 95 % CI) were light-intensity physical activity (per 1 h/week increase: 1·04; 1·01, 1·07) and insulin resistance (homeostasis model assessment of insulin resistance score >6·1 v. <4·1: 4·62; 1·37, 15·51). Increased consumption of a traditional dietary pattern based on fish and seafood, low-fat cereals, fruits and vegetables was a protective factor (0·49; 0·31, 0·79). All variables were modelled together and adjusted for age and sex. CONCLUSIONS: The high prediabetes prevalence found in the Comcáac community is alarming because it represents a large number of people who are at risk for type 2 diabetes. The identification of modifiable factors associated with prediabetes that are specific to this population may be useful for designing effective strategies to prevent prediabetes.

Randomized double-blind controlled clinical trial of the blood pressure-lowering effect of fermented milk with Lactococcus lactis: A pilot study.

The blood pressure-lowering effect of fermented milk with Lactococcus lactis NRRL B-50571 was evaluated in a double-blind randomized controlled clinical trial with prehypertensive subjects. Participants were randomized into 2 groups (n = 18 each group): one group treated with fermented milk with Lactococcus lactis NRRL B-50571 and a control group treated with artificially acidified milk. Results revealed that during daily consumption of fermented milk for 5 wk, systolic [(116.55 ± 12.26 mmHg vs. 124.77 ± 11.04 mmHg) and diastolic blood pressure (80.7 ± 9 vs. 84.5 ± 8.5 mmHg)] from the fermented milk group was lower than the control group. Additionally, triglyceride, total cholesterol, and low-density lipoprotein in blood serum were lower in the fermented milk group than in the control group. Results demonstrated that daily consumption of fermented milk with Lactococcus lactis (NRRL B-50571) had a blood pressure-lowering effect on prehypertensive subjects. Regular consumption of this product may be used as a potential functional food.

A restricted population of CB1 cannabinoid receptors with neuroprotective activity.

The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.

Economic Feasibility of Wireless Sensor Network-Based Service Provision in a Duopoly Setting with a Monopolist Operator.

We analyze the feasibility of providing Wireless Sensor Network-data-based services in an Internet of Things scenario from an economical point of view. The scenario has two competing service providers with their own private sensor networks, a network operator and final users. The scenario is analyzed as two games using game theory. In the first game, sensors decide to subscribe or not to the network operator to upload the collected sensing-data, based on a utility function related to the mean service time and the price charged by the operator. In the second game, users decide to subscribe or not to the sensor-data-based service of the service providers based on a Logit discrete choice model related to the quality of the data collected and the subscription price. The sinks and users subscription stages are analyzed using population games and discrete choice models, while network operator and service providers pricing stages are analyzed using optimization and Nash equilibrium concepts respectively. The model is shown feasible from an economic point of view for all the actors if there are enough interested final users and opens the possibility of developing more efficient models with different types of services.

Antineoplastic treatment effect on bone mineral density in Mexican breast cancer patients.

BACKGROUND: Breast cancer is the most deadly malignancy in Mexican women. Although treatment has improved, it may significantly affect bone mineral status in those who receive it. The aim of this study was to assess the impact of cancer treatment on bone mineral density (BMD) and bone mineral content (BMC), in patients with breast cancer and explore the interaction of menopausal status and clinical stage with cancer treatment on such changes. METHODS: A quasi-experimental design was applied with measurements before and after a chemotherapy treatment in 40 patients with primary diagnosis of invasive breast cancer. BMD and body composition measurements were taken by dual X-ray absorptiometry (DXA) and changes in these variables due to therapy were analyzed using mixed regression for repeated measurements. RESULTS: Significant loss was found in femoral neck and L2-L4 BMD (p < 0.001). Patients diagnosed with osteopenia or osteoporosis received calcium + vitamin D supplementation (600 mg/200 IU day). It showed a protective effect in the decrease of femoral neck BMD and total BMC. BMD loss in both femoral neck and L2-L4 BMD was higher in premenopausal women: 0.023 g/cm2 in femoral neck and 0.063 g/cm2 in L2-L4 (p < 0.001), while in postmenopausal women BMD loss was 0.015 g/cm2 in femoral neck and 0.035 g/cm2 in L2-L4 (p = 0.021 and p = 0.001 respectively). Change in lumbar spine BMD was prominent in premenopausal women with advanced clinical stage (IIB, IIIA, IIIB): 0.066 g/cm2 (p = 0.003). CONCLUSION: The antineoplastic breast cancer treatment with chemotherapy had a negative impact on BMD, in premenopausal women overall, although a differential effect was found according to clinical stage and calcium supplementation status.