Among the many signalling lipids, endocannabinoids are increasingly recognized for their important roles in neuronal and glial development. Recent experimental evidence suggests that, during neuronal ...differentiation, endocannabinoid signalling undergoes a fundamental switch from the prenatal determination of cell fate to the homeostatic regulation of synaptic neurotransmission and bioenergetics in the mature nervous system. These studies also offer novel insights into neuropsychiatric disease mechanisms and contribute to the public debate about the benefits and the risks of cannabis use during pregnancy and in adolescence.
The mass concentration of atmospheric particulate matter (PM) has been systematically used in epidemiological studies as an indicator of exposure to air pollutants, connecting PM concentrations with ...a wide variety of human health effects. However, these effects can be hardly explained by using one single parameter, especially because PM is formed by a complex mixture of chemicals. Current research has shown that many of these adverse health effects can be derived from the oxidative stress caused by the deposition of PM in the lungs. The oxidative potential (OP) of the PM, related to the presence of transition metals and organic compounds that can induce the production of reactive oxygen and nitrogen species (ROS/RNS), could be a parameter to evaluate these effects. Therefore, estimating the OP of atmospheric PM would allow us to evaluate and integrate the toxic potential of PM into a unique parameter, which is related to emission sources, size distribution and/or chemical composition. However, the association between PM and particle-induced toxicity is still largely unknown. In this commentary article, we analyze how this new paradigm could help to deal with some unanswered questions related to the impact of atmospheric PM over human health.
Honey bees are critical pollinators in ecosystems and agriculture, but their numbers have significantly declined. Declines in pollinator populations are thought to be due to multiple factors ...including habitat loss, climate change, increased vulnerability to disease and parasites, and pesticide use. Neonicotinoid pesticides are agonists of insect nicotinic cholinergic receptors, and sub-lethal exposures are linked to reduced honey bee hive survival. Honey bees are highly dependent on circadian clocks to regulate critical behaviors, such as foraging orientation and navigation, time-memory for food sources, sleep, and learning/memory processes. Because circadian clock neurons in insects receive light input through cholinergic signaling we tested for effects of neonicotinoids on honey bee circadian rhythms and sleep. Neonicotinoid ingestion by feeding over several days results in neonicotinoid accumulation in the bee brain, disrupts circadian rhythmicity in many individual bees, shifts the timing of behavioral circadian rhythms in bees that remain rhythmic, and impairs sleep. Neonicotinoids and light input act synergistically to disrupt bee circadian behavior, and neonicotinoids directly stimulate wake-promoting clock neurons in the fruit fly brain. Neonicotinoids disrupt honey bee circadian rhythms and sleep, likely by aberrant stimulation of clock neurons, to potentially impair honey bee navigation, time-memory, and social communication.
Aim
High blood pressure (BP) is associated with gut microbiota dysbiosis. The aim of this study was to investigate whether changes in gut microbiota induced by exchanging the gut microbiota between ...spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) alter the gut‐immune system interaction inducing changes in vascular function and BP.
Methods
Twenty‐week‐old recipient WKY and SHR were orally gavaged with donor faecal contents from WKY or SHR. In additional experiments, we used a design to determine whether blockade of B7‐dependent costimulation with CTLA4‐Ig or blockade of IL‐17 with IL‐17‐neutralizing antibody could prevent hypertension caused by faecal microbiota transplantation (FMT) from SHR to WKY.
Results
Correlation analyses identified the bacterial abundance of Turicibacter and S24‐7_g that, respectively, positively and negatively correlated with systolic BP. FMT from WKY rats to SHR rats reduced basal systolic BP, restored the imbalance between Th17/Treg in mesenteric lymph nodes (MLNs) and aorta, and improved endothelial dysfunction and vascular oxidative status found in SHR transplanted with SHR faeces. FMT from SHR to WKY increased CD80 and CD86 mRNA levels and T cells activation in MLNs, circulating T cells, aortic T cell infiltration, impaired endothelial function and increased basal SBP. These effects were abolished by blockade of B7‐dependent costimulation with CTLA4‐Ig. IL‐17a neutralizing antibody reduced SBP and improved endothelial dysfunction induced by FMT from SHR to WKY.
Conclusion
Gut microbiota is an important factor involved in the control of BP, as a consequence of its effect in T‐cell activation in gut immune system and vascular T‐cells accumulation.
Seasonal day length has been linked to the prevalence of mood disorders, and however, the mechanisms underlying this relationship remain unknown. Previous work in our laboratory has shown that ...developmental exposure to seasonal photoperiods has enduring effects on the activity of mouse dorsal raphe serotonergic neurons, their intrinsic electrical properties, as well as on depression and anxiety‐related behaviors. Here we focus on the possible ionic mechanisms that underlie the observed programming of the electrophysiological properties of serotonin neurons, focusing on the twin‐pore K + channels TREK‐1 and TASK‐1 that set resting membrane potential and regulate excitability. Pharmacological inhibition of TREK‐1 significantly increased spike frequency in Short and Equinox photoperiods, but did not further elevate the firing rate in slices from Long photoperiod mice, suggesting that TREK‐1 function is reduced in Long photoperiods. In contrast, inhibition of TASK‐1 resulted in increases in firing rates across all photoperiods, suggesting that it contributes to setting excitability, but is not regulated by photoperiod. We then quantified Kcnk2 mRNA levels specifically in dorsal raphe 5‐HT neurons using triple‐label RNAscope. We found that Long photoperiod significantly reduced levels of Kcnk2 in serotonin neurons co‐expressing Tph2, and Pet‐1. Photoperiodic effects on the function and expression of TREK‐1 were blocked in melatonin 1 receptor knockout (MT‐1KO) mice, consistent with previous findings that MT‐1 signaling is necessary for photoperiodic programming of dorsal raphe 5‐HT neurons. Taken together these results indicate that photoperiodic regulation of TREK‐1 expression and function plays a key role in photoperiodic programming the excitability of dorsal raphe 5‐HT neurons.
Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses
. By contrast, astrocytes are under neuronal control ...through specific neurotransmitter receptors
. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB
) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB
receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB
receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.
SCOPE: The cardiovascular effects of probiotics Lactobacillus fermentum CECT5716 (LC40), or L. coryniformis CECT5711 (K8) plus L. gasseri CECT5714 (LC9) (1:1) in spontaneously hypertensive rats (SHR) ...were evaluated. METHODS AND RESULTS: Ten Wistar Kyoto rats (WKY) and 30 SHR were randomly assigned to four groups (n = 10): a control WKY group, a control SHR groups, an SHR group treated with LC40, and an SHR treated with K8/LC9 group for 5 weeks (at a dose of 3.3 × 10¹⁰ colony‐forming units/day in drinking water). Long‐term administration of probiotics reduced systolic blood pressure. The consumption of K8/LC9 mixture significantly reduced the cardiac and renal hypertrophy. Both groups of probiotics reversed the impaired aortic endothelium‐dependent relaxation to acetylcholine observed in SHR. They also abolished the increased aortic superoxide levels by reducing the increased toll‐like receptor‐4 mRNA levels and NADPH oxidase activity found in SHR. K8/LC9 consumption also increased endothelial nitric oxide synthase phosphorylation. Probiotic treatments induced a change in the cecum microbiota of SHR, with higher counts of the Lactobacillus spp. cluster, and lower counts of Bacteriodes spp. and Clostridium spp. CONCLUSION: Probiotics exert cardiovascular protective effects in genetic hypertension related to the improvement of vascular pro‐oxidative and pro‐inflammatory status.
Cardiovascular Effects of Flavonoids Sánchez, Manuel; Romero, Miguel; Gómez-Guzmán, Manuel ...
Current medicinal chemistry,
01/2019, Letnik:
26, Številka:
39
Journal Article
Recenzirano
Cardiovascular Disease (CVD) is the major cause of death worldwide, especially in Western society. Flavonoids are a large group of polyphenolic compounds widely distributed in plants, present in a ...considerable amount in fruit and vegetable. Several epidemiological studies found an inverse association between flavonoids intake and mortality by CVD. The antioxidant effect of flavonoids was considered the main mechanism of action of flavonoids and other polyphenols. In recent years, the role of modulation of signaling pathways by direct interaction of flavonoids with multiple protein targets, namely kinases, has been increasingly recognized and involved in their cardiovascular protective effect. There are strong evidence, in in vitro and animal experimental models, that some flavonoids induce vasodilator effects, improve endothelial dysfunction and insulin resistance, exert platelet antiaggregant and atheroprotective effects, and reduce blood pressure. Despite interacting with multiple targets, flavonoids are surprisingly safe. This article reviews the recent evidence about cardiovascular effects that support a beneficial role of flavonoids on CVD and the potential molecular targets involved.
Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The ...present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue. Studies conducted with MiaPaCa2 and Panc1 cell lines showed that cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB(2) cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo. Knockdown experiments using selective small interfering RNAs showed the involvement of p8 via its downstream endoplasmic reticulum stress-related targets activating transcription factor 4 (ATF-4) and TRB3 in Delta(9)-tetrahydrocannabinol-induced apoptosis. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.
The CB₁ cannabinoid receptor, the main target of Δ⁹-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as ...evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB₁ signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB₁ receptor genetic ablation, and CB₁-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB₁ expression-rescue strategy in a CB₁-null background. Early and selective CB₁ reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB₁-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB₁-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB₁ signaling.
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