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Alzheimer disease is a neurodegenerative disease characterized by the presence of senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have revealed that extracellular ATP, through its selective receptor P2X7 (P2X7R), is essential to neuroinflammation and neurotoxicity induced by Aβ. P2X7R is upregulated on microglial cells around the senile plaques. This upregulation progressively rises with age and is parallel with an accumulation of senile plaques and also correlates with the synaptic toxicity detected both in animal models reproducing AD and human patients of AD. Furthermore, the late onset of the first AD-associated symptoms suggests that aging associated-changes may be relevant to the disease progression. Thus, microglia motility and its capacity to respond to exogenous ATP stimulus decrease with aging. To evaluate whether the P2X7R age related-changes on microglia cells may be relevant to the AD progression, we generated a new transgenic mouse model crossing an Aβ peptide mouse model, J20 mice and the P2X7R reporter mice EGFP. Our results indicate that neuroinflammation induced by Aβ peptide causes changes in the P2X7R distribution pattern, increasing it s expression in microglial cells at advanced and late stages, when microgliosis occurs, but not in the early stages, in the absence of microgliosis. In addition, we found that P2X7R activation promotes microglial cells migration to senile plaques but decreases their phagocytic capacity. Moreover, we found a significant reduction of P2X7R transcription on neuronal cells at the early and advanced stages, but not at the late stages. Since previous studies have reported that either pharmacological inhibition or selective downregulation of P2X7R significantly improve behavioral alterations and reduce the incidence and size of senile plaques in the early and advanced stages of AD, the results presented here provide new evidence, indicating that this therapeutic approach could be also efficient in the late stages of the disease.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by a progressive cognitive decline associated with global brain damage. Initially, intracellular paired helical filaments composed by hyperphosphorylated tau and extracellular deposits of amyloid-β (Aβ) were postulated as the causing factors of the synaptic dysfunction, neuroinflammation, oxidative stress, and neuronal death, detected in AD patients. Therefore, the vast majority of clinical trials were focused on targeting Aβ and tau directly, but no effective treatment has been reported so far. Consequently, only palliative treatments are currently available for AD patients. Over recent years, several studies have suggested the involvement of the purinergic receptor P2X7 (P2X7R), a plasma membrane ionotropic ATP-gated receptor, in the AD brain pathology. In this line, altered expression levels and function of P2X7R were found both in AD patients and AD mouse models. Consequently, genetic depletion or pharmacological inhibition of P2X7R ameliorated the hallmarks and symptoms of different AD mouse models. In this review, we provide an overview of the current knowledge about the role of the P2X7R in AD.

Background Over recent years, increasing evidence suggests a causal relationship between neurofibrillary tangles (NFTs) formation, the main histopathological hallmark of tauopathies, including Alzheimer’s disease (AD), and the ubiquitin–proteasome system (UPS) dysfunction detected in these patients. Nevertheless, the mechanisms underlying UPS failure and the factors involved remain poorly understood. Given that AD and tauopathies are associated with chronic neuroinflammation, here, we explore if ATP, one of the danger-associated molecules patterns (DAMPs) associated with neuroinflammation, impacts on AD-associated UPS dysfunction. Methods To evaluate if ATP may modulate the UPS via its selective P2X7 receptor, we combined in vitro and in vivo approaches using both pharmacological and genetic tools. We analyze postmortem samples from human AD patients and P301S mice, a mouse model that mimics pathology observed in AD patients, and those from the new transgenic mouse lines generated, such as P301S mice expressing the UPS reporter Ub G76V -YFP or P301S deficient of P2X7R. Results We describe for the first time that extracellular ATP-induced activation of the purinergic P2X7 receptor (P2X7R) downregulates the transcription of β5 and β1 proteasomal catalytic subunits via the PI3K/Akt/GSK3/Nfr2 pathway, leading to their deficient assembly into the 20S core proteasomal complex, resulting in a reduced proteasomal chymotrypsin-like and postglutamyl-like activities. Using UPS-reported mice (UbGFP mice), we identified neurons and microglial cells as the most sensitive cell linages to a P2X7R-mediated UPS regulation. In vivo pharmacological or genetic P2X7R blockade reverted the proteasomal impairment developed by P301S mice, which mimics that were detected in AD patients. Finally, the generation of P301S;UbGFP mice allowed us to identify those hippocampal cells more sensitive to UPS impairment and demonstrate that the pharmacological or genetic blockade of P2X7R promotes their survival. Conclusions Our work demonstrates the sustained and aberrant activation of P2X7R caused by Tau-induced neuroinflammation contributes to the UPS dysfunction and subsequent neuronal death associated with AD, especially in the hippocampus.

Early weaning in intensive pig production induces stress, compromising gastrointestinal health. Poor fat digestion results from the piglets’ underdeveloped digestive system. Dietary emulsifiers can enhance fat utilization, and glyceryl polyethylene glycol ricinoleate (GPGR) has been shown to improve pig performance. This study evaluated GPGR’s effects on intestinal health in weaned piglets in a commercial production farm. A total of 380 just weaned (21 days old) piglets were divided in two groups of 190 animals each (in four replicates) that received either a basal diet (control) or a basal diet + 350 g/ton GPGR pharmaceutical formulation as top dress. Blood samples were collected at pre-established days, and intestinal sampling occurred 15 days post-weaning. Plasma cortisol, citrulline, intestinal morphology, mucus quality, enzymatic activity, volatile fatty acids (VFAs), and cecal microbiota were analyzed. GPGR did not alter plasma cortisol but increased citrullinemia (P: 0.024), suggesting greater enterocyte functional mass. GPGR piglets showed improved intestinal morphology (greater villus height, villus height:crypt depth ratio, and intestinal absorption area, p < 0.05) and higher enzymatic maltase activity (p ≤ 0.014). VFAs, bacterial adherence to mucus, and goblet cell counts were unaffected. Dietary GPGR increased Firmicutes and Actinobacteria (P: 0.014 and P: 0.045, respectively) while reducing Proteobacteria (p < 0.001). In conclusion, dietary GPGR promotes intestinal health in weaned piglets by improving epithelial structure, digestive function, and microbiota balance, representing a promising strategy to support piglets in overcoming the early nursery phase.

This study aimed to investigate the effect of three different doses of estradiol-17b onovulation and subsequent luteal development and function in llamas. Twenty-three llamaswere examined daily by transrectal ultrasonography until the detection of an ovulatoryfollicle (≥8mm). Thereafter, animals were divided into five groups: Control (n = 3; treatedwith 1.6ml of saline solution), GnRH group (n = 6, treated with an intravenous injectionof 8.4 μg Buserelin), and estradiol groups that received 0.6mg (E1, n = 4), 1mg (E2,n = 4), or 1.6mg (E3, n = 6) of estradiol-17b intravenously. Detection of ovulationwas based on ultrasonographic visualization of disappearance of the largest follicleand subsequent presence of a newly formed corpus luteum (CL) and progesteroneconcentration exceeding 1 ng ml−1. Daily blood samples were collected to determineplasma progesterone concentration. Ovulation rate was 0% for control and E1 groups,25% for E2 group, and 100% for GnRH and E3 groups. Differences in the meanCL diameter between GnRH and E3 groups were not statistically significant. Plasmaprogesterone concentration was similar between groups during the different days inovulated animals. However, the day that the plasma progesterone concentration wasabove 1 ng ml−1 and the day that the highest plasma progesterone concentration wasachieved differed among E3 and GnRH groups, occurring later in females treated withestradiol. In conclusion, an injection of estradiol-17b is capable of inducing ovulation inllamas and the response depends on the dose used. Most of the animals required thehighest tested dose (1.6mg) to induce the ovulatory process. Although the CL diameterin females induced to ovulate with estradiol was similar to that in llamas induced toovulate with a GnRH analog, the rise in plasma progesterone concentration above 1 ngml−1 and the peak progesterone concentration were attained 1 day later in the estradioltreated females.

Objectives Sodium hypochlorite (NaOCl) exhibits antimicrobial activity. However, it is associated with negative effects in endodontics, such as cytotoxicity and alterations in the mechanical properties of root dentin, leading to the search for new alternatives. Hypochlorous acid (HClO) exhibits antimicrobial activity and low cytotoxicity as irrigation solution. Therefore, the aim of this study was to evaluate the influence of HClO on the mechanical properties of root dentin. Material and Methods Samples were obtained from 120 mandibular bovine incisors, which were distributed into four experimental groups: microhardness (30 teeth/60 samples), flexural strength (15 teeth/60 samples), cohesive strength (15 teeth/60 samples), and fracture resistance (60 teeth/60 samples). For all tests, the samples were subdivided into six groups (n = 10): G1: distilled water (DW); G2:1% NaOCl; G3:2.5% NaOCl; G4:5.25% NaOCl; G5:250 ppm HClO; and G6:500 ppm HClO. The irrigation protocol was set at 30 min. Then, a Vickers tester was used to evaluate microhardness, and flexural strength, cohesive strength, and fracture resistance were evaluated in a universal testing machine. One‐way ANOVA and Tukey tests were used for multiple comparisons in all evaluations (α = 5%). Results The highest microhardness was observed in DW, 250 ppm HClO and 500 ppm HClO, with no statistical differences between them (p > 0.05). The highest flexural and cohesive strength were observed in DW, 1% NaOCl, HClO 250 ppm, and HClO 500 ppm, with no statistical differences between them (p > 0.05). Regarding the fracture resistance, there were no statistical differences between all groups (p > 0.05). Conclusion It was concluded that HClO preserved the mechanical properties of root dentin.

The aim of this study was to characterize the temporal association between follicular waves and circulating concentrations of 17β-estradiol (E2) and IGF1 in llamas. Follicular waves could be clearly divided in three phases: growth, plateau and regression; with a mean duration of 18.8 ± 0.32 days. All follicular waves showed overlapping, so that as one dominant follicle was regressing, another one was growing. E2 plasma concentration showed a wavelike pattern, similar to that followed by the dominant follicle; reaching its maximum concentration at the end of the growth phase and decreasing at the end of the plateau phase. IGF1 also showed variations during the follicular wave. It tended to increase during the growth phase and decreased toward Days 14 and 16. IGF1 reached its maximum concentration before E2 did (5 ± 0.8 vs. 7.2 ± 0.5 days after wave emergence) and before the maximum follicular diameter was attained (10.2 ± 0.46 days after wave emergence). Both hormones started to rise again in coincidence with the development of a new follicular wave. The observed profiles allow to suggest that IGF1 could have a role on folliculogenesis and ovarian steroideogenesis in llamas, as reported for other species.

Background: There is increasing evidence that the brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of mood disorders and that its peripheral levels represent a reliable mirror of its concentration in the brain. The aim of the present study was to measure BDNF plasma levels in patients affected by major depression and to explore the possible relationship between the biological parameter and characteristics of the illness. Method: BDNF plasma levels were evaluated in 30 inpatients suffering from major depression, according to DSM-IV criteria, by means of a commonly employed ELISA method. The clinical characteristics were assessed by the Hamilton Rating Scale for Depression (HRSD) and the Clinical Global Impression Scale. Results: BDNF plasma levels were significantly lower in the patients with the severest illness compared with the others, and the same was true for patients with dissociative symptoms, severe sleep disturbance and recurrent depression. A significant and negative correlation was observed between the biological parameter and the retardation factor score of the HRSD. Conclusion: These findings suggest that low BDNF levels are related to both recurrence and severity of depression, as well as to symptoms typical of dysfunctions of the hypothalamic-pituitary-adrenal axis.

Neoplasms of the mammary gland represent the most frequent tumor type in the female dog, and according to the histologic criteria, approximately 50% of them are malignant. In the most aggressive cases of mammary cancer, surgery is not enough to warrant a favorable outcome, and adjuvant therapies are needed to improve the patient's overall survival. The aim of the present study was to evaluate the effects of two peptides on proliferation of a canine mammary cancer cell line derived from a simple carcinoma. The cell line CMT-U27 was grown in 96-well plates, at two cell densities (4 × 10 and 8 × 10 cells/well). Cultures were treated with oxytocin (OT) or desmopressin at five concentrations (10, 50, 100, 500, and 1000 nM). After 72 h of incubation, cell proliferation was determined by the MTT assay. Results showed that with 4 × 10 cells/well, OT at 50, 500, and 1000 nM was growth inhibitory for the cells, being statistically significant at 1000 nM. On the contrary, no antiproliferative effect was observed with 10 or 100 nM. At 8 × 10 cells/well, OT showed a significant antiproliferative effect only with the highest concentration (1000 nM). Desmopressin at 4 × 10 cells/well decreased cell viability at concentrations of 50, 100, 500, and 1000 nM (statistically significant with the highest concentration), while no effect was observed with 10 nM. With 8 × 10 cells/well, this peptide reduced cell growth at 100, 500, and 1000 nM. In conclusion, we suggest that these peptides may be potential and promising compounds for the treatment of dogs with simple carcinomas of the mammary gland. studies are required to confirm this hypothesis.