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This systematic review and meta-analysis aimed to evaluate the analgesic efficacy and adverse effects of celecoxib after total knee arthroplasty. Keywords in the PubMed and Scopus databases were used to find article abstracts. Each included clinical trial was assessed using the Cochrane Collaboration risk of bias tool, and we extracted data on postoperative pain assessment using the Visual Analogue Scale (VAS) at rest, ambulation, and active range of motion, rescue analgesic intake, and adverse effects. Inverse variance tests with mean differences were used to analyze the numerical variables. The Mantel–Haenszel statistical method and the odds ratio were used to evaluate the dichotomous data. According to this qualitative assessment (n = 482), two studies presented conclusions in favor of celecoxib (n = 187), one showed similar results between celecoxib and the placebo (n = 44), and three clinical trials did not draw conclusions as to the effectiveness of celecoxib versus the placebo (n = 251). Moreover, the evaluation of the rescue analgesic intake showed that the patients receiving celecoxib had a lower intake compared to patients receiving a placebo (n = 278, I2 = 82%, p = 0.006, mean difference = −6.89, 95% IC = −11.76 to −2.02). In conclusion, the pooled analysis shows that administration of celecoxib alone results in a decrease in rescue analgesic consumption compared to a placebo after total knee surgery.

Abstract Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Abstract Mammary gland development occurs primarily in adulthood, undergoing extensive expansion during puberty followed by cycles of functional specialization and regression with every round of pregnancy/lactation/involution. This process is ultimately driven by the coordinated proliferation and differentiation of mammary epithelial cells. However, the endogenous molecular factors regulating these developmental dynamics are still poorly defined. Endocannabinoid signaling is known to determine cell fate-related events during the development of different organs in the central nervous system and the periphery. Here, we report that the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) plays a pivotal role in adult mammary gland development. Specifically, it is required for luminal lineage specification in the mammary gland, and it promotes hormone-driven secretory differentiation of mammary epithelial cells by controlling the endogenous levels of anandamide and the subsequent activation of cannabinoid CB1 receptors. Together, our findings shed light on the role of the endocannabinoid system in breast development and point to FAAH as a therapeutic target in milk-production deficits.

The avocado cv. Hass requires a suitable rootstock for optimal development under water stress. This study evaluated the performance of two avocado rootstocks (ANRR88 and ANGI52) grafted onto cv. Hass under four water stress conditions, 50% and 25% deficit, and 50% and 25% excess during the nursery stage. Plant height, leaf area (LA), dry matter (DM), and Carbon (OC) content in the roots, stems, and leaves were measured. Root traits were evaluated using digital imaging, and three vegetation indices (NDVI, CIRE, and MTCI) were used to quantify stress. The results showed that genotype significantly influenced the response to water stress. ANRR88 exhibited adaptation to moderate to high water deficits. ANGI52 adapted better to both water deficit and excess, and showed greater root exploration. LA and DM reductions of up to 60% were observed in ANRR88, suggesting a higher sensitivity to extreme changes in water availability. More than 90% of the total OC accumulation was observed in the stem and roots. The NDVI and the MTCI quantified the presence and levels of stress applied, and the 720 nm band provided high precision and speed for detecting stress. These insights are crucial for selecting rootstocks that ensure optimal performance under varying water availability, enhancing productivity and sustainability.

The incidence of type 2 diabetes (T2D) is rising, and finding new treatments is important. C. sativa is a plant suggested as a potential treatment for T2D, but how it works needs to be clarified. This study explored the pharmacological mechanism of C. sativa in treating T2D. We identified the active compounds in C. sativa and their targets. From there, we examined the genes associated with T2D and found overlapping genes. We conducted an enrichment analysis and created a protein–protein and target–compound interactions network. We confirmed the binding activities of the hub proteins and compounds with molecular docking. We identified thirteen active compounds from C. sativa, which have 150 therapeutic targets in T2D. The enrichment analysis showed that these proteins are involved in the hormone, lipid, and stress responses. They bind transcription factors and metals and participate in the insulin, PI3K/Akt, HIF-1, and FoxO signaling pathways. We found four hub proteins (EGFR, ESR1, HSP90AA1, and SRC) that bind to the thirteen bioactive compounds. This was verified using molecular docking. Our findings suggest that C. sativa’s antidiabetic action is carried out through the insulin signaling pathway, with the participation of HIF-1 and FoxO.

Recent research on maize root architecture has made significant progress, but further research is needed to optimize methods for efficient and accurate acquisition of root architecture data. This study aimed to assess the effectiveness of digital imaging for root phenotyping of Zea mays L. Field experiments were carried out at two locations in the province of Antioquia, Colombia, in 2019 and 2020 to analyze root architecture variables of 12 genotypes of maize. Two methodologies were used: manual phenotyping and digital image analysis. Pearson’s correlation coefficients among variables were estimated. Principal Component Analysis (PCA) was used to summarize and uncover clustering patterns in the multivariate data set. The results indicated correlations between diameter (r = 0.94) and manually measured root diameter. The manually measured right and left root angles correlated with image-derived root angle at r = 0.92 and 0.88, respectively, and root length at r = 0.62. The PCA highlighted that the digital method explained the highest proportion of variation in root areas and diameters, while the manual method dominated in root angle variables. These results corroborate a feasible method to optimize root architecture phenotyping for research questions. This protocol can be adopted under the automatic analysis with REST software for acquiring images of variables associated with roots’ angle, length, and diameter.

Abstract Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease.

Abstract The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.

Background: Dental caries is a dynamic, multifactorial disease that destroys teeth and can affect anyone’s quality of life because it can cause tooth loss and make chewing difficult. Dental caries involves various factors, such as Streptococcus mutans and host factors. Currently, adjuvant therapies, such as curcumin, have emerged, but how they work has not been adequately described. Therefore, this work aims to identify the molecular mechanism of curcumin in caries and Streptococcus mutans. Methods: We obtained differentially expressed genes from a GEO dataset, and curcumin targets were obtained from other databases. The common targets were analyzed according to gene ontology enrichment, key genes were obtained, and binding to curcumin was verified by molecular docking. Results: Our analysis showed that curcumin presents 134 therapeutic targets in caries. According to the gene ontology analysis, these targets are mainly involved in apoptosis and inflammation. There are seven key proteins involved in the action of curcumin on caries: MAPK1, BCL2, KRAS, CXCL8, TGFB1, MMP9, and IL1B, all of which spontaneously bind curcumin. In addition, curcumin affects metabolic pathways related to lipid, purine, and pyrimidine metabolism in Streptococcus mutans. Conclusions: Curcumin affects both host carious processes and Streptococcus mutans.

Gastric cancer (GC) is the second most common cause of death of any cancer-related cases in the world, and is also in the top 5 most common malignancy cancers in general. There are plenty of well-distributed treatments, offering better hygiene, more robust and complete nutrition, and the eradication of pathogens such as Helicobacter pylori. Currently, there is still the need for more treatments, especially those of lower cost, like those coming from already easily available products. Quercetin (QRC) is a natural phenolic compound present in a wide variety of products, e.g., in plants like Hibiscus sabdariffa, onions, grapes, broccoli, and citrus fruits. This product has been shown to have great potential therapeutic effects, and it has also been suggested that it could be useful in combating different types of cancer; however, information regarding the targets or mechanisms that QRC has on cancer cells is still unclear. Therefore, this study aims to identify the targets that QRC has, like anti-cancer treatment for GC using different bio-informatic tools and databases. From MalaCards and SwissTargetPrediction, both QRC and GC molecular targets were defined, and then they were matched with the Venny 2.1.0 platform. From this, 31 genes were gathered, and then they were analyzed using the ShinnyGo0.77 and DAVID-Bioinformatic Resources. Furthermore, StringDB was used to identify the protein—protein interactions, and Citoscape 3.6.0 12 hub genes were obtained. Those hub genes were then subject to Gene Expression Profiling Interactive Analysis and TISIDB. Finally, molecular docking studies were performed using the SwissDock database. The results suggest that, according to the gene ontology data, QRC has a relationship with the regulation of cell death, response to stress, cell motility, response to amyloid-beta, cellular response to reactive oxygen species, and apoptotic processes. Some genes like EGFR were correlated with an abundance of CD8 and Neutrophil infiltration but didn’t show to improve the survival rate. Furthermore, molecular docking results show that QRC can bind to multiple molecules of interest. These results complement some of the currently available information alluding to the effectiveness of plants rich with QRC as part of the treatment used for different kinds of cancer, but it also suggests a plethora of new targets that this molecule has in GC, while at the same time giving a clearer idea of the mechanisms that are affected in GC by QRC. However, as with any other study that primarily uses bioinformatic tools, these final results are to be used for more direct and precise research, especially if experimental protocols are used.

Excitotoxicity has been linked to the pathogenesis of several serious degenerative ocular diseases. Long-term overactivation of the NMDA receptor by glutamate in retinal ganglion cells (RGCs) results in degeneration, apoptosis and loss of function leading to blindness. NMDA receptor antagonists have been proposed as a pharmacological blockage of glutamate excitotoxicity. However, an inhibition of the pathway activated by glutamate receptors has intolerable side effects. An interesting pharmacological alternative would be the use of antiapoptotic compounds as RGCs’ neuroprotective active substances. Several mechanisms have been proposed to explain neuroprotection, including anti-inflammatory and scavenging activities. Here, the role of dexamethasone in neuroprotection was studied. For this purpose, original controlled release systems composed of microparticles containing dexamethasone with or without vitamin E and human serum albumin (HSA) were designed. The particles were prepared by the solid-in-oil-in-water (S/O/W) emulsion–evaporation technique. After properly characterization of the particles, they were intravitreally injected into an rat model of acute ocular excitotoxicity injury. The functionality of the retina was determined by electroretinography and RGCs were counted after cell immunohistochemistry. These microparticulate systems showed the ability to maintain normal electroretinal activity and promoted significant protection of RGCs. Through this proof of concept, we demonstrated that dexamethasone could be a useful anti-inflammatory agent to avoid the progression of degenerative ocular diseases. Furthermore, when administered in controlled release systems that provide low concentrations during prolonged periods of time, not only can the patient’s comfort be increased but the cytotoxicity of the drugs can also be avoided.

Objetivos. Determinar los cambios en las características clínicas y desenlaces intrahospitalarios de los pacientes hospitalizados por COVID-19 en un hospital privado de Caracas durante dos años de pandemia. Materiales y métodos. Estudio retrospectivo, observacional, de pacientes hospitalizados por COVID-19. Se investigó la correspondencia entre las olas de ingresos hospitalarios con las variantes circulantes del SARS-CoV-2 en la población general del Distrito Capital y estado Miranda. Resultados. Se incluyeron 1025 pacientes (569 hombres y 456 mujeres), con edad promedio de 62,9 DE: 16,2 años. Cuatro olas de ingresos hospitalarios fueron identificadas: primera (marzo-noviembre 2020) 150/1025 (14,6%) casos; segunda (diciembre-2020 a mayo-2021) 415/1025 (40,5%) casos; tercera (junio-diciembre 2021) 344/1025 (33,6%) casos; cuarta (enero-febrero 2022) 116/1025 (11,3%) casos. La edad promedio fue mayor en la cuarta ola (primera 64,0±15,7, segunda 61,4±15,8, tercera 62,1±16,5, y cuarta ola 68,5±16,4), mientras que la proporción de pacientes masculinos (primera 66,7%, segunda 58,8%, tercera 50,3%, y cuarta 44,8%), los pacientes con enfermedad grave-crítica (primera 65,3%, segunda 57%, tercera 51,7% y cuarta 44,8%), la estadía intrahospitalaria (primera 9,1±6,0, segunda 9,0±7,3, tercera 8,8±7,7, y cuarta 6,9±5,0 días), los ingresos a la UCI (primera 23,3%, segunda 15,7%, tercera 14,0%, y cuarta 11,2%; p=0,027) y la mortalidad (primera 21.8%, segunda 10,7%, tercera 9,1%, y cuarta 7,1%; p

Increasing evidence indicates that a key factor in neurodegenerative diseases is the activation of the unfolded protein response (UPR) caused by an accumulation of misfolded proteins in the endoplasmic reticulum (ER stress). Particularly, in Huntington's disease (HD) mutant huntingtin (mHtt) toxicity involves disruption of the ER-associated degradation pathway and loss of the ER protein homeostasis leading to neuronal dysfunction and degeneration. Besides the role of the UPR in regulating cell survival and death, studies that demonstrate the contribution of sustained UPR activation, particularly of PERK signaling, in memory disturbances and synaptic plasticity deficiencies are emerging. Given the contribution of hippocampal dysfunction to emotional and cognitive deficits seen in HD, we have analyzed the involvement of ER stress in HD memory alterations. We have demonstrated that at early disease stages, ER stress activation manifested as an increase in GRP78 and CHOP is observed in the hippocampus of R6/1 mice. Genetic reduction of GRP78 expression resulted in preventing hippocampal-dependent memory alterations but no motor deficits. Accordingly, hippocampal neuropathology namely, dendritic spine loss and accumulation of mHtt aggregates was ameliorated by GRP78 reduction. To elucidate the signaling pathways, we found that the inactivation of PERK by GSK2606414 restored spatial and recognition memories in R6/1 mice and rescued dendritic spine density in CA1 pyramidal neurons and protein levels of some specific immediate early genes. Our study unveils the critical role of the GRP78/PERK axis in memory impairment in HD mice and suggests the modulation of PERK activation as a novel therapeutic target for HD intervention.

Abstract Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptor-deficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cell-autonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.

The aim of this systematic review and meta-analysis was to evaluate the analgesic effect of different doses of tapentadol immediate release (IR) and its adverse effects after a bunionectomy. Pubmed, Cochrane, Lilacs, Medline, and Imbiomed were used to identify abstracts of scientific publications related to the keywords of this systematic review (PROSPERO ID CRD42023437295). Moreover, the risk of bias in all included articles was assessed using the Cochrane Collaboration risk of bias tool. Data on the sum of pain intensity, total pain relief, global assessment, and adverse effects were extracted. The statistical method of inverse variance with means difference was used to evaluate the numerical data and the Mantel–Haenszel and Odd Ratio test to analyze the dichotomous data. In addition, the number needed to treat, the number needed to harm, and the 95% confidence intervals were calculated. A qualitative evaluation (n = 2381) was carried out according to the conclusions of the authors. Tapentadol (n = 1772) was more effective in relieving postoperative pain than the placebo (n = 609) after a bunionectomy. In addition, the analgesic efficacy of IR tapentadol (n = 1323) versus the placebo (n = 390) was evaluated in a total of 1713 patients using a global evaluation of the treatments. All three doses of IR tapentadol showed better results compared to the placebo after a bunionectomy. Finally, the adverse effects have a direct relationship with the dose, and the greatest number of adverse effects are most observed with tapentadol IR 100 mg (n = 2381). It is concluded that tapentadol IR (100 mg) leads to the best satisfaction score in this meta-analysis.

Introduction The increased risk of myocardial infarction (MI) in type 2 diabetes mellitus (T2DM) is well documented. Polymorphisms in APOA1 and APOB genes allow us to identify new genetic markers in the Mexican population with T2DM and MI. Material and methods We studied 135 patients with DMT2 and MI (DI); another 85 non-infarcted diabetic individuals with DMT2 but without previous ischemic events (NID) and 242 healthy subjects (HS). All three groups were selected with the aim to investigate the association between the polymorphisms and infarction when T2DM is present or absent. Results -75 G>A polymorphism: Differences were found in genotype distribution between DI and NID individuals (OR = 2.01, 95% CI: 1.117–3.623, p = 0.019) with an increased risk for A in the dominant model (OR = 1.77, 95% CI: 1.020–3.084, p = 0.042); also concentrations of ApoA-I for A/A were lower in comparison with G/A (p = 0.038) and LDL-C and HDL-C levels were lower in G/A compared to G/G carriers. 83 C>T polymorphism of APOA1: For DI individuals, HDL-C was lower in T/T compared to C/C and triglyceride levels were lower in C/T compared to C/C carriers. Conclusions The -75 G>A APOA1 polymorphism could be considered as a susceptibility factor for myocardial infarction in individuals with T2DM and 2488 C>T APOB polymorphism is associated with changes in HDL-C and LDL-C and triglycerides in the same group.

El trabajo que se presenta tiene el objetivo de explicar los alcances de la herramienta de georreferenciación de cuencas (SIATL), que proporciona el Instituto Nacional de Estadística y Geografía (INEGI) .

Abstract Acid sphingomyelinase deficiency (ASMD) leads to cellular accumulation of sphingomyelin (SM), neurodegeneration, and early death. Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM‐KO) mice and a ASMD patient. High SM reduced expression of the eCB receptor CB1 in neuronal processes and induced its accumulation in lysosomes. Activation of CB1 receptor signaling, through inhibition of the eCB‐degrading enzyme fatty acid amide hydrolase (FAAH), reduced SM levels in ASM‐KO neurons. Oral treatment of ASM‐KO mice with a FAAH inhibitor prevented SM buildup; alleviated inflammation, neurodegeneration, and behavioral alterations; and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We also found CB1 receptor downregulation in neurons of a mouse model and a patient of another sphingolipid storage disorder, Niemann–Pick disease type C (NPC). We showed the efficacy of FAAH inhibition to reduce SM and cholesterol levels in NPC patient‐derived cells and in the brain of a NPC mouse model. Our findings reveal a pathophysiological crosstalk between neuronal SM and the eCB system and offer a new treatment for ASMD and other sphingolipidoses.

Seed uniformity and stability testing, and multiplication, are key steps in the seed supply chain of the common bean (Phaseolus vulgaris L.) and other crops. Optimizing agronomical practices in these phases can ultimately ensure seed quality and availability, and germplasm prospective utilization. However, farmers have rarely standardized seed testing and propagation protocols in local common bean landraces conserved in situ. An example of this is the Liborino variety (var.), a promising yellow Andean common bean known for its presumably high digestibility and adaptation to the local conditions of the Cauca river canyon (northwest Andes of Colombia), but likely experiencing genetic erosion after decades of suboptimal propagation. Therefore, this work intended to evaluate and select locally adapted genotypes of common bean var. Liborino for commercial use, to be later multiplied, evaluated by participatory breeding, and eventually shared with farmers. Specifically, we evaluated 44 accessions of var. Liborino common bean in six adaption and yield field trials in the Cauca river canyon at 1100 and 1400 m a.s.l, and in AGROSAVIA’s “La Selva” research station at 2100 m a.s.l. In parallel, we carried out standardized seed multiplication of a Liborino genotype using best practices to guarantee uniformity and stability. From the 44 accessions, nine were well adapted to the tested local conditions. Four of these accessions exhibited a bush type growth habit, while the remaining five were climbers. The trials revealed maximum average extrapolated yields of up to 1169.4 ± 228.4 kg ha−1 for the bush types (G8152) and up to 1720.0 ± 588.4 kg ha−1 for the climbers (G51018), both at 2100 m a.s.l. Three climbing accessions matched farmers’ expectations for seed coat color and shape, according to a participatory selection exercise. Uniform and stable seed of the selected genotype was delivered in 2022 to 39 farmers, ~6.5 kg of seeds per farmer. Our results will allow implementing bean genetic improvement pipelines, promoting var. Liborino commercialization, and boosting the economic and sustainable development of the rural communities in the Cauca river canyon. Seed uniformity testing and multiplication pipelines must be extended to other bean landraces conserved in situ.

Este artículo aborda el estudio de las secuelas y daños que se generan en personas adultas mayores ocasionados por el abandono y falta de convivencia con sus familiares, particularmente el caso de aquellos que se encuentran ingresados en casas de retiro o también llamados asilos. El deterioro emocional y psicológico que padecen por la frágil o nula relación con familiares desencadena una serie de eventos negativos tales como falta de apetito, depresión, aislamiento, negatividad a realizar actividades grupales o las inherentes a su óptima motricidad. Esta serie de eventos, los lleva a presentar patologías que terminan por acabar con su vida a corto plazo. Empero, los eventos negativos antes aludidos, pueden ser anulados a través de la implementación de los círculos restaurativos, en los que las personas adultas mayores cuenten con la oportunidad de expresar sus sentimientos y emociones de manera libre, espontánea y respetuosa, que les propicie una mejor comunicación y relación con familiares. Afianzando con esto, el reforzamiento de los lazos afectivos, el mejoramiento emocional y de salud del adulto mayor.

Abstract Background The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids. Methods We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro. Results Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis. Conclusions The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.

Choosing a suitable prosthesis to restore the functionality of the hip joint is a complex problem. The stem geometries, materials, and type of hip damage are critical factors for avoiding potential issues (aseptic loosening, fracture, and natural wear and tear). Comparing the available stems to select the best option is not straightforward because of the various loads and boundary conditions used in the tests, making the process difficult to compare the advantages and disadvantages among them. This work proposes stem assessment using a standardized base (generated from a literature review and ISO standards) to compare the stem geometries and present a new hybrid design to improve performance using the best qualities of the implants reported in the literature review. Sixteen hip prostheses were evaluated with the finite element method (FEM) using the same boundary and loading conditions through multi-objective analysis (von Mises stress and strain). Consequently, a hybrid geometry proposal was obtained by assessing specific points through the stem length (medial and lateral region) to define the cross-section (trapezoidal) and the new profile. The new hybrid implant proposal presented a stress reduction of 9.6% when compared to the reference implant P2-T (the implant with the best behavior) in the most critical activity (activity 4) using a titanium alloy. A similar stress reduction of 9.98% was obtained using ASTM F2996-13 and ISO 7206–4:2010(E) standards.

Background: Periodontitis (P) is a chronic inflammatory disease characterized by the destruction of periodontium support tissue generated by different immuno-inflammatory mechanisms, including the RANK/RANKL/OPG and the IL-23/IL-17 axis. Methods: The study was performed with healthy subjects (HS) and patients with periodontitis. Plasma samples were obtained from peripheral blood and the gingival tissue (GT) during periodontal surgery. The ELISA technique was used to evaluate the levels of IL-23, IL-17A, IL-23R, and IL-17RA. Results: In the plasma, a significant decrease in IL-17A was observed in patients with periodontitis than HS. In the GT, IL-23, IL-17A, and IL-17RA levels were increased in periodontitis patients; on the contrary, IL-23R levels were decreased in periodontitis patients when compared with HS. Finally, several positive correlations were found: soluble IL-17RA (sIL-17RA) levels in plasma between the percentage of radiographic bone loss (RBL%), and IL-23 with IL-17A in gingival tissue. Conclusions: The detection of the IL-23/IL-17A axis in gingival tissue and plasma provides us with more information on the behavior of this axis in a localized way in the periodontal microenvironment, in contrast to the systemic levels evaluated according to the new classification of periodontitis.

Glaucoma is a group of chronic irreversible neuropathies that affect the retina and the optic nerve. It is considered one of the leading causes of blindness in the world. Although it can be due to various causes, the most important modifiable risk factor is the elevated intraocular pressure (IOP). In this case, the treatment of choice consists of instilling antihypertensive formulations on the ocular surface. The chronicity of the pathology, together with the low bioavailability of the drugs that are applied on the ocular surface, make it necessary to instill the formulations very frequently, which is associated, in many cases, with the appearance of dry eye disease (DED). The objective of this work is the design of topical ocular formulations capable of treating glaucoma and, at the same time, preventing DED. For this, two liposome formulations, loaded with brimonidine or with travoprost, were Tadeveloped using synthetic phospholipids and enriched by the addition of compounds with osmoprotective activity. The proposed formulations not only presented physicochemical characteristics (size, pH, osmolarity, surface tension, and viscosity) and encapsulation efficiency values (EE% of 24.78% and ≥99.01% for brimonidine and travoprost, respectively) suitable for ocular surface administration, but also showed good tolerance in human corneal and conjunctival cell cultures, as well as an in vitro osmoprotective activity. The hypotensive effect of both liposomal formulations was evaluated in normotensive albino New Zealand rabbits, showing a faster and longer lasting reduction of intraocular pressure in comparison to the corresponding commercialized products used as control. According to these results, the hypotensive liposomal formulations combined with osmoprotective agents would result in a very promising platform for the treatment of glaucoma and the simultaneous protection of the ocular surface.

The state of Sonora is the main grape production area in Mexico. Grapevine trunk diseases (GTD) are serious disease in this region. During the springs of 2017 and 2018, symptoms of yellow and wilted leaves, and necrotic buds, were observed in several vineyards in Sonora. Affected plants had numerous small, black and bright acervuli. This study aimed to identify the causative agent of this disease. Isolates were obtained from small pieces of damaged plant parts, and were cultured on potato dextrose agar. The developing mycelium was white but turned greyish white after 3 d. Multi-shaped black mucilaginous droplets appeared in the cultures after 2 d, and the agar in Petri dishes was completely covered with mycelium after 7 d, and the colonies had five or six rings with large numbers of conidiomata. Conidia were hyaline or light cream, fusiform, oval or ellipsoid, with truncated bases and narrow almost pointed apices, and were 6–10 mm long and 2–3 mm wide. Phylogenetically analysed concatenated sequences of the DNA from two representative isolates, from the internal transcribed spacer region, and large ribosomal subunit, showed they were in a separate clade which aligned with several strains of Greeneria uvicola, confirming the presumptive morphological identity of the isolates. This cosmopolitan ascomycete is responsible for bitter rot of grapes, but the role of this fungus as a cause of grapevine trunk diseases is little known. Pathogenicity tests of the isolates were performed on 1-year-old ‘Passion Fire’ grapevines plants, one of the new cultivars planted in Sonora. All of strains G. uvicola were pathogenic, and the fungus was recovered from the lesions, fulfilling Koch’s postulates. This is the first report on the pathogenicity of G. uvicola in wood tissues of Vitis vinifera in Mexico.

The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ9-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ9-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ9-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.

Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

In this work, the effect of the proportion of a hyperbranched polyester polyol (HBP) of fourth generation on the structural, thermal, rheological, morphological and mechanical properties of tapioca starch/HBP blends (TPS) was evaluated. For this purpose, the ratios of starch:HBP employed to prepare the TPS were: 30:70 (TPS30), 40:60 (TPS40) and 50:50 (TPS50). Using infrared (IR) analysis, it was observed that the presence of HBP produced a displacement at the absorptions of the C-OH, C-O and C-O-C bonds of the TPS. The X-ray diffraction (DRX) analysis showed that the starch crystallinity is A and B type, which increased with the HBP amount. The glass transition temperature (Tg) of the TPS, increased with the HBP content, but the thermal stability and viscosity (at an angular frequency of 1 Hz) presented an opposite behavior. The scanning electronic microscopy analysis (SEM) revealed that the granular structure of the starch was not completely destructured.

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.

Maxims of Experience in Mexican Case Law As máximas da experiência na jurisprudência mexicana El texto analiza un corpus de tesis jurisprudenciales generadas por los Tribunales de Amparo mexicanos, en los que se advierten distintas funciones en el uso del concepto “máximas de la experiencia”, para lo cual utiliza dos criterios de clasificación: 1) como concepto autónomo: para valoración probatoria, para colmar lagunas normativas, inferir conclusiones fácticas, generar un parámetro objetivo de verdad, sustentar una decisión razonable, y 2) en la correlación con otros conceptos de valoración probatoria del tipo: método científico, reglas de la lógica, pensar reflexivo, sana crítica, prueba libre, sentido común. De ello se concluye que la jurisprudencia mexicana trata a las “máximas de la experiencia” como un tópico de lugar común, tanto desde el punto de vista lingüístico como epistemológico. Para citar este artículo / To reference this article / Para citar este artigo Héctor Manuel Guzmán Ruíz, “Las máximas de la experiencia en la jurisprudencia mexicana”, en Dikaion 28, 2 (2019), 355-384. DOI: https://doi.org/10.5294/dika.2019.28.2.6 Recibido: 11/03/2019 Aceptado: 16/06/2019 Publicado: 24/10/2019

Alterations of the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are causally involved in a subset of malformations of cortical development (MCDs) ranging from focal cortical dysplasia (FCD) to hemimegalencephaly and megalencephaly. These MCDs represent a frequent cause of refractory pediatric epilepsy. The endocannabinoid system -especially cannabinoid CB1 receptor- exerts a neurodevelopmental regulatory role at least in part via activation of mTORC1 signaling. Therefore, we sought to characterize the possible contribution of endocannabinoid system signaling to FCD. Confocal microscopy characterization of the CB1 receptor expression and mTORC1 activation was conducted in FCD Type II resection samples. FCD samples were subjected to single nucleotide polymorphism screening for endocannabinoid system elements, as well as CB1 receptor gene sequencing. Cannabinoid CB1 receptor levels were increased in FCD with overactive mTORC1 signaling. CB1 receptors were enriched in phospho-S6-positive cells including balloon cells (BCs) that co-express aberrant markers of undifferentiated cells and dysplastic neurons. Pharmacological regulation of CB1 receptors and the mTORC1 pathway was performed in fresh FCD-derived organotypic cultures. HU-210-evoked activation of CB1 receptors was unable to further activate mTORC1 signaling, whereas CB1 receptor blockade with rimonabant attenuated mTORC1 overactivation. Alterations of the endocannabinoid system may thus contribute to FCD pathological features, and blockade of cannabinoid signaling might be a new therapeutic intervention in FCD.