Sustained hypoxia (SH) in mice induces changes in the respiratory pattern and increase in the parasympathetic tone to the heart. Among adenosine G‐protein‐coupled receptors (GPCRs), the A2A receptors ...are especially important in mediating adenosine actions during hypoxia due to their expression in neurons involved with the generation and modulation of the autonomic and respiratory functions. Herein, we performed an in vivo evaluation of the baseline cardiovascular and respiratory parameters and their changes in response to SH in knockout mice for A2A receptors (A2AKO). SH produced similar and significant reductions in mean arterial pressure and heart rate in both wild‐type (WT) and A2AKO mice when compared to their respective normoxic controls. Mice from WT and A2AKO groups submitted to normoxia or SH presented similar cardiovascular responses to peripheral chemoreflex activation (KCN). Under normoxic conditions A2AKO mice presented a respiratory frequency (fR) significantly higher in relation to the WT group, which was reduced in response to SH. These data show that the lack of adenosine A2A receptors in mice does not affect the cardiovascular parameters and the autonomic responses to chemoreflex activation in control (normoxia) and SH mice. We conclude that the A2A receptors play a major role in the control of respiratory frequency and in the tachypnoeic response to SH in mice.
New Findings
What is the central question of this study?
Are cardiovascular and respiratory parameters and their changes in response to sustained hypoxia (SH) altered in adenosine A2A receptor knockout mice?
What is the main finding and its importance?
Cardiovascular parameters and their changes in response to SH were not altered in A2AKO mice. The respiratory frequency in A2AKO was higher than in WT mice. In response to SH the respiratory frequency increased in WT, while it was reduced in A2AKO mice. A2A receptors play a major role in the modulation of respiratory frequency and in the tachypnoeic response to SH in mice.
Sustained hypoxia (SH) in mice induces changes in the respiratory pattern and increase in the parasympathetic tone to the heart. Among adenosine G-protein-coupled receptors (GPCRs), the A
receptors ...are especially important in mediating adenosine actions during hypoxia due to their expression in neurons involved with the generation and modulation of the autonomic and respiratory functions. Herein, we performed an in vivo evaluation of the baseline cardiovascular and respiratory parameters and their changes in response to SH in knockout mice for A
receptors (A
KO). SH produced similar and significant reductions in mean arterial pressure and heart rate in both wild-type (WT) and A
KO mice when compared to their respective normoxic controls. Mice from WT and A
KO groups submitted to normoxia or SH presented similar cardiovascular responses to peripheral chemoreflex activation (KCN). Under normoxic conditions A
KO mice presented a respiratory frequency (f
) significantly higher in relation to the WT group, which was reduced in response to SH. These data show that the lack of adenosine A
receptors in mice does not affect the cardiovascular parameters and the autonomic responses to chemoreflex activation in control (normoxia) and SH mice. We conclude that the A
receptors play a major role in the control of respiratory frequency and in the tachypnoeic response to SH in mice. NEW FINDINGS: What is the central question of this study? Are cardiovascular and respiratory parameters and their changes in response to sustained hypoxia (SH) altered in adenosine A
receptor knockout mice? What is the main finding and its importance? Cardiovascular parameters and their changes in response to SH were not altered in A
KO mice. The respiratory frequency in A
KO was higher than in WT mice. In response to SH the respiratory frequency increased in WT, while it was reduced in A
KO mice. A
receptors play a major role in the modulation of respiratory frequency and in the tachypnoeic response to SH in mice.
Display omitted
•Hypoxia and A2A receptors knockout do not affect the neuronal membrane properties.•A2A receptors modulate the spontaneous glutamatergic currents.•Hypoxia enhances the evoked ...glutamatergic currents by a non-presynaptic mechanism.•A2A receptors do not modulate the evoked glutamatergic currents under normoxia.•A2A receptors are required to enhance evoked glutamatergic currents after hypoxia.
The first synapses of the afferents of peripheral chemoreceptors are located in the Nucleus Tractus Solitarius (NTS) and there is evidence that short-term sustained hypoxia (SH – 24 h, FiO2 0.1) facilitates glutamatergic transmission in NTS neurons of rats. Adenosine is an important neuromodulator of synaptic transmission and hypoxia contributes to increase its extracellular concentration. The A2A receptors mediate the excitatory actions of adenosine and are active players in the modulation of neuronal networks in the NTS. Herein, we used knockout mice for A2A receptors (A2AKO) and electrophysiological recordings of NTS neurons were performed to evaluate the contribution of these receptors in the changes in synaptic transmission in NTS neurons of mice submitted to SH. The membrane passive properties and excitability of NTS neurons were not affected by SH and were similar between A2AKO and wild-type mice. The overall amplitude of spontaneous glutamatergic currents in NTS neurons of A2AKO mice was lower than in Balb/c WT mice. SH increased the amplitude of evoked glutamatergic currents of NTS neurons from WT mice by a non-presynaptic mechanism, but this enhancement was not observed in NTS neurons of A2AKO mice. Under normoxia, the amplitude of evoked glutamatergic currents was similar between WT and A2AKO mice. The data indicate that A2A receptors (a) modulate spontaneous glutamatergic currents, (b) do not modulate the evoked glutamatergic transmission in the NTS neurons under control conditions, and (c) are required for the enhancement of glutamatergic transmission observed in the NTS neurons of mice submitted to SH.
Tuberculosis (TB) is a granulomatous disease that has affected humanity for thousands of years. The production of cytokines, such as IFN-γ and TNF-α, is fundamental in the formation and maintenance ...of granulomas and in the control of the disease. Recently, the introduction of TNF-α-blocking monoclonal antibodies, such as Infliximab, has brought improvements in the treatment of patients with chronic inflammatory diseases, but this treatment also increases the risk of reactivation of latent tuberculosis. Our objective was to analyze, in an in vitro model, the influence of Infliximab on the granulomatous reactions and on the production of antigen-specific cytokines (TNF-α, IFN-γ, IL-12p40, IL-10 and IL-17) from beads sensitized with soluble Bacillus Calmette-Guérin (BCG) antigens cultured in the presence of peripheral blood mononuclear cells (PBMC) from TB patients. We evaluated 76 individuals, with tuberculosis active, treated and subjects with positive PPD. Granuloma formation was induced in the presence or absence of Infliximab for up to 10 days. The use of Infliximab in cultures significantly blocked TNF-α production (p <0.05), and led to significant changes in granuloma structure, in vitro, only in the treated TB group. On the other hand, there was a significant reduction in the levels of IFN-γ, IL-12p40, IL-10 and IL-17 after TNF-α blockade in the three experimental groups (p <0.05). Taken together, our results demonstrate that TNF-α blockade by Infliximab directly influenced the structure of granuloma only in the treated TB group, but negatively modulated the production of Th1, Th17 and regulatory T cytokines in the three groups analyzed.
Renal cell carcinoma (RCC) is the most common type of cancer in kidney and is often diagnosed in advanced stages. Until now, there is no reliable biomarker to assess tumor prognosis during ...histopathological diagnosis. The Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) overexpression has been suggested as prognostic indicator for RCC, however, its protein profile needs to be clarified. This study investigated the MTHFD2 expression in different RCC cohorts, associating it with tumor characteristics and prognostic factors. Gene expression comparisons between non-neoplastic (NN) and tumor samples, as well as patients' survival analysis, were assessed using KM-Plotter tool. MTHFD2 protein pattern was evaluated in 117 RCC by immunohistochemistry and associations with prognosis, clinical and pathological data were investigated. The tumors exhibited higher MTHFD2 transcript levels than NN, being even higher in the metastatic group. Opposite gene expression patterns were found among clear cell renal cell carcinoma (ccRCC) and pappilary renal cell carcinoma (pRCC) subtypes, showing higher and lower expressions compared to NN samples respectively. Overexpression was associated with shorter overall survival for ccRCC and pRCC subtypes, and shorter recurrence-free survival for pRCC. The immunolabeling profile varied according to tumor subtypes, with lower intensity and expression scores in ccRCC compared to pRCC and to chromophobe renal cell carcinoma (chRCC). MTHFD2 protein expression was associated with larger tumors and higher Fuhrman grades. Although prognostic value of protein immunostaining was not confirmed, patients with higher MTHFD2 tended to have lower survival rates in the pRCC group. The results highlight MTHFD2 different patterns according to RCC histological subtypes, revealing marked variations at both the genetic and protein levels. The mRNA indicated tumor prognosis, and greater expression in the tumor samples. Although MTHFD2 immunolabeling suggests tumor aggressiveness, it needs to be validated in other cohorts as potential prognostic factor.
Research regarding polyphenols has gained prominence over the years because of their potential as pharmacological nutrients. Most polyphenols are flavanols, commonly known as catechins, which are ...present in high amounts in green tea. Catechins are promising candidates in the field of biomedicine. The health benefits of catechins, notably their antioxidant effects, are related to their chemical structure and the total number of hydroxyl groups. In addition, catechins possess strong activities against several pathogens, including bacteria, viruses, parasites, and fungi. One major limitation of these compounds is low bioavailability. Catechins are poorly absorbed by intestinal barriers. Some protective mechanisms may be required to maintain or even increase the stability and bioavailability of these molecules within living organisms. Moreover, novel delivery systems, such as scaffolds, fibers, sponges, and capsules, have been proposed. This review focuses on the unique structures and bioactive properties of catechins and their role in inflammatory responses as well as provides a perspective on their use in future human health applications.
The study aim was to determine a range of relevant persistent and emerging pollutants in oysters produced in an aquaculture facility located in an important production area, to assure their safety ...for human consumption. Pollutants, including 16 PAHs, 3 butyltins (BTs), 29 flame retardants (FRs, including organophosphate and halogenated FRs), 35 pesticides (including 9 pyrethroid insecticides) and 13 personal care products (PCPs, including musks and UV filters), were determined in oysters' tissues collected during one year in four seasonal sampling surveys. The seasonal environmental pollution on the production site was evaluated by water and sediment analysis. Furthermore, oysters' nutritional quality was also assessed and related with the consumption of healthy seafood, showing that oysters are a rich source of protein with low fat content and with a high quality index all year around. Results showed that most analysed pollutants were not detected either in oyster tissues or in environmental matrixes (water and sediments). The few pollutants detected in oyster tissues, including both regulated and non-legislated pollutants, such as a few PAHs (fluorene, phenanthrene, anthracene, fluoranthene, pyrene and indenopyrene), FRs (TPPO, TDCPP, DCP, BDE-47, BDE-209 and Dec 602) and PCPs (galaxolide, galaxolidone, homosalate and octocrylene), were present at low levels (in the ng/g dw range) and did not represent a significant health risk to humans. The observed seasonal variations related to human activities (e.g. tourism in summer) highlights the need for environmental protection and sustainable resource exploration for safe seafood production.
Display omitted
•Bioaccumulation of organic contaminants assessed in aquaculture farmed oysters.•Emerging and persistent organic contaminants detected, generally at low levels•Most frequently detected families were halogenated flame retardants and personal care products.•Seasonal variations related with human activities were detected.•Results highlights the need for environmental protection and sustainable resource exploration.
The autonomic profile of mice submitted to sustained hypoxia (SH) was not yet fully evaluated. Herein, we characterized the cardiovascular and autonomic profile of conscious freely moving mice ...submitted to SH using two sequential experimental protocols to evaluate the parasympathetic and sympathetic tone to the heart and the sympathetic tone to the vascular resistance. In the first protocol the sequence of antagonists was methyl-atropine followed by propranolol and then by prazosin, while in the second protocol the sequence was propranolol followed by methyl-atropine and then by prazosin. In SH the baseline heart rate was significantly lower than in control mice and the antagonism of the parasympathetic and sympathetic tone to the heart in both experimental protocols indicated an increased parasympathetic tone in SH mice and no changes in the sympathetic tone. Antagonism of the sympathetic tone to the vascular resistance with prazosin produced similar changes in arterial pressure in control and SH mice. Altogether these findings support the concept that mice submitted to SH present a significant increase in the parasympathetic but not in the sympathetic tone, which may explain why the baseline arterial pressure was not increased in SH mice.
•Autonomic profile of awake mice submitted to sustained hypoxia (SH) was evaluated by sequential pharmacological antagonists.•Baseline heart rate in SH mice was lower and the tachycardic response to methyl-atropine was greater than in control mice.•Fall in mean arterial pressure in response to prazosin was similar in control and SH mice.•Parasympathetic tone to the heart of mice submitted to SH is increased while the overall sympathetic tone is not.•These findings contribute to explain why mice, different of rats, are not hypertensive in response to SH.
Inhibition of dopamine transporter (DAT) by GBR12909 has been proposed as a pharmacological model of mania related to bipolar disorder (BD). Here we tested the hypothesis that GBR12909 injection ...impairs habituation and induces hyperlocomotion in mice, along with changes in cytokines and neurotrophic factors levels, as observed in BD patients. We also tested if lithium carbonate, sodium valproate and aripiprazole prevent GBR12909-induced locomotion. Male Swiss mice received GBR12909 (15 mg/kg) injections and locomotor responses were quantified in an open field. Cytokines and neurotrophic factors levels were assessed in the prefrontal cortex, striatum and hippocampus 30 min and 24 h after injections. Pre-treatments with lithium, valproate or aripiprazole were performed with single and repeated injection protocols. GBR12909 prevented motoric habituation and increased basal locomotion in habituated mice in the open field. This compound also induced changes in IL-2 and BDNF levels in prefrontal cortex; IL-2, IL-4 and IL-10 in striatum; and IL-10, IL-4, IFN-γ and NGF in hippocampus. GBR12909-induced hyperlocomotion was attenuated by lithium (12.5–100 mg/kg), but not valproate (75–300 mg/kg), and prevented by aripiprazole (0.1–10 mg/kg). Repeated injections of these drugs (twice a day for 3 days), however, failed to inhibit hyperlocomotion. The main limitations of the protocols in this study are the analysis of locomotion as the only behavioral parameter, changes in immune factors that may overlap with other psychiatric disorders and the lack chronic drug injections. Despite of these limitations, this study adds to previous literature suggesting DAT inhibition as a potential animal model of mania related to BD.
Display omitted
•Cacti represent the most important radiation of succulent angiosperms.•This is the first study using ddRAD-Seq data to follow up hybridization in Cactaceae.•The studied species are ...highly promiscuous in sympatric areas.•We inferred low genomic introgression and selection favoring parental genotypes.
Hybridization and introgression between species in contact/hybrid zones provide important insight into the genetic and ecological mechanisms of speciation. Cactaceae represents the most important radiation of true succulent angiosperms in the New World. This diversification continues to date, with species experiencing few intrinsic barriers to gene flow and the frequent occurrence of natural hybridization. Here, we used RAD-Seq single-nucleotide polymorphism (SNP) data to investigate the genetic architecture of hybridization in four hybrid zones hosting Melocactus concinnus and four congeneric species (M. ernestii, M. glaucescens, M. paucispinus, and M. zehntneri). Our results revealed that M. concinnus is highly promiscuous in sympatric areas and hybridizes with various species distributed in Morro do Chapéu (Diamantina Plateau, Bahia), eastern Brazil. However, the contemporary genomic introgression among the investigated species is very low (c. 2–5%), confirming that even in the face of hybridization, Melocactus species maintain their genetic integrity. The genomic cline approach showed a large fraction of loci deviating from a model of neutral introgression, where most of the loci are consistent with selection favoring parental genotypes. Our results suggest the occurrence of weak premating but strong postmating reproductive isolation in the analyzed cactus species. Furthermore, as most of the Melocactus species are restricted in distribution, hybridization might negatively affect their integrity if hybrids replace the parental species.
PDF
