Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases

Background: Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are signalling lipids which belong to the class of endocannabinoids (ECs) and exert their actions by activating cannabinoid receptor type-1 (CB1) and type-2 (CB2). These receptors are involved in many physiological and pathological processes in the central nervous system (CNS) and in peripheral organs. Despite many potent and selective ligands for cannabinoid receptors have been generated over the last two decades, this class of compounds achieved only a very limited therapeutic success, mainly because of the CB1- mediated side effects. Methods: The compounds and results presented in this review article have been gathered from an extensive research in public databases for patents, clinical trials and scientific literature. Reference to patent numbers, clinical trial registry numbers, websites and scientific articles is provided in the text and/or in the reference section. Results: Over the last 10-15 years, many inhibitors for the main EC hydrolytic enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α,β-hydrolase domain-6 (ABHD6) and -12 (ABHD12) have been synthesized and characterized in vitro and in vivo. Additionally, other targets have been explored for the modulation of the endocannabinoid system (ECS). Among them, several novel inhibitors for COX-2, diacylglycerol lipases and the putative endocannabinoid membrane transporter have been described in the literature. Polypharmacological approaches which combine mild or reversible inhibition of at least two of these targets are also under investigation. Conclusions: The ECS offers several therapeutic opportunities beyond the direct activation of cannabinoid receptors. The modulation of EC levels in vivo represents an interesting therapeutic perspective for several CNS-related diseases. Based on the literature and patent literature this review provides an overview of the different classes of inhibitors for FAAH, MAGL, ABHDs and COX-2 used as tool compounds and for clinical development with a special focus on CNS-related diseases

Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders

Since the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases. Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery

Environmental impacts of a material recovery facility in a Life Cycle Perspective

The study aims to evaluate the environmental performances of an integrated material recovery facility (MRF), which has a crucial role in the waste management plan of a region in the middle of Italy, characterized by a low level (less than 20%) of household source separation and separate collection [1]. The facility, which is able to treat about 30 kt/y of mixed waste, has three main units: a mechanical sorting platform, bio-cells for tunnel composting, and a landfill. The output streams of the sorting platform are the ferrous metals and mixed plastics, which are sent to the recycling processes, the solid recovered fuel (SRF), which is utilized in an external combustion-based waste-to-energy plant, and a low-quality organic fraction, which is treated in the on-site composting unit. The solid residues generated by these processes are about a half of the input stream, and are disposed in the annexed landfill. The bio-cells for tunnel composting are in operation since 2014, and so far produces just a low-quality compost, utilized for landfill capping, and a leachate, sent to an external wastewater treatment plant (WTP). The landfill produces a leachate, which is treated in the WTP, and a biogas, which is collected (with an efficiency of about 60%), and sent to a gas engine, having an electric energy conversion efficiency of 38%. Please click Additional Files below to see the full abstract

Changes in Morpho-Anatomical and Eco-Physiological Responses of Viburnum tinus L. var lucidum as Modulated by Sodium Chloride and Calcium Chloride Salinization

Salinity in water and soil is among the major constraints to the cultivation of ornamental crops since it can affect their growth and aesthetic value. A greenhouse experiment was carried out to assess whether the application of two different salts (80mM NaCl or 53.3mM CaCl2, with a final ionic concentration of 160 mM) could differently modulate the anatomical and physiological acclimation of an important ornamental species such as Viburnum tinus L. var. lucidum. Eco-physiological analyses (e.g., leaf gas exchange and chlorophyll a fluorescence emission) were performed and leaves were subjected to light microscopy analysis to quantify functional anatomical traits through digital image analysis. Results showed that the two iso-osmotic solutions induced different structuremediated physiological alterations in V. tinus plants. Photosynthesis was lowered by CaCl2 treatments (-58%) more than by NaCl (-37%), also due to the occurrence of photodamage apart from stomatal limitations. Neither Na+ nor Cl- exhibited toxic effects in leaf lamina structure which was reflected in the limited reduction in dry matter accumulation. Overall data were interpreted focusing on the coordination among leaf structural and functional traits suggesting that the fine control of functional anatomical traits contributes to physiological acclimation to both stressful condition

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects. Methods: Ts65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition. Results: The analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed. Discussion: These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals

How Leaf Vein and Stomata Traits Are Related with Photosynthetic Efficiency in Falanghina Grapevine in Different Pedoclimatic Conditions

The increase in severe drought events due to climate change in the areas traditionally suitable for viticulture is enhancing the need to understand how grapevines regulate their photosynthetic metabolism in order to forecast specific cultivar adaptive responses to the changing environment. This study aims at evaluating the association between leaf anatomical traits and eco-physiological adjustments of the 'Falanghina' grapevine under different microclimatic conditions at four sites in southern Italy. Sites were characterized by different pedoclimatic conditions but, as much as possible, were similar for plant material and cultivation management. Microscopy analyses on leaves were performed to quantify stomata and vein traits, while eco-physiological analyses were conducted on vines to assess plant physiological adaptation capability. At the two sites with relatively low moisture, photosynthetic rate, stomatal conductance, photosystem electron transfer rate, and quantum yield of PSII, linear electron transport was lower compared to the other two sites. Stomata size was higher at the site characterized by the highest precipitation. However, stomatal density and most vein traits tended to be relatively stable among sites. The number of free vein endings per unit leaf area was lower in the two vineyards with low precipitation. We suggest that site-specific stomata and vein traits modulation in Falanghina grapevine are an acclimation strategy that may influence photosynthetic performance. Overall in-depth knowledge of the structure/function relations in Falanghina vines might be useful to evaluate the plasticity of this cultivar towards site-specific management of vineyards in the direction of precision viticulture

Determination of total vanadium and vanadium(V) in groundwater from Mt. Etna and estimate of daily intake of vanadium(V) through drinking water.

Vanadium(V) can be found in natural waters in the form of V(IV) and V(V) species, which have different biological properties and toxicity. The purpose of this study was to determine the concentrations of total V and V(V) in groundwater from the area of Mt. Etna and to assess the estimated daily intake (EDI) of V(V) of adults and children through drinking water. Water was sampled monthly at 21 sites in 2011. Total vanadium was determined by inductively coupled plasma-mass spectrometry (ICP-MS) and speciation by ion chromatography-ICP-MS (IC-ICP-MS). The concentration of V(V) species ranged from 62.8 to 98.9% of total V, with significantly higher concentrations in samples from the S/SW slope of Mt. Etna. The annual mean concentrations of total V exceeded the Italian legal limit of 140 μg/L at four sites on the S/SW slope. In the absence of thresholds for V(V) intake, only the Environmental Protection Agency (EPA) has calculated a reference dose. Children's EDI of V(V) at the sites with the higher V concentrations exceeded EPA thresholds (9 μg/kg/day). In particular, we found in Camporotondo, Mascalucia, Ragalna and San Pietro Clarenza sites children's EDIs of 11, 9.3, 11 and 9.9, respectively. The EDI of V(V) was significantly higher than the literature range (0.09–0.34 μg/kg/day)

Counteracting the negative effects of copper limitations through the biostimulatory action of a tropical plant extract in grapevine under pedo-climatic constraints

In southern Mediterranean areas, vineyards are facing the combination of increasing air temperature, drought and frequency of extreme events (e.g., heat waves) due to climate change. Since most of the berry growth and ripening phases occur during the aridity period, such environmental constraints are responsible for limitations in yield and berry quality. Within this scenario, to achieve vineyard sustainability, renewed approaches in vineyard management have been proposed and the use of plant biostimulants seems a prominent and environmental friendly practice. The aim of this study was to test four combinations of a tropical plant extract and conventional chemicals for disease control on morpho-anatomical, physiological, biochemical and berry quality in Vitis vinifera L. subsp. vinifera “Aglianico.” In particular, we aimed to evaluate the possibility to counteract the negative effects of the reductions in copper distribution, by applying the tropical plant extract enriched with: micronutrients, enzymes involved in the activation of natural defense, aminoacids, and vitamins. The halved dose of Cu in combination with the tropical plant extract allowed maintaining a reduced vegetative vigor. In the second year of treatment, the addition of the plant extract significantly improved leaf gas exchanges and photochemistry as well as the synthesis of photosynthetic pigments. At berry level, the plant extract induced an increase in phenolics accompanied by a decrease in soluble sugars. The overall results showed that the expected differences in growth performance and productivity in vines are linked to different eco-physiological and structural properties induced by the various treatments. The tropical plant extract also primed plant defenses at the leaf and fruit levels, mainly due to modifications of some structural and biochemical traits, respectively

Hyperphosphorylation of JNK-interacting Protein 1, a Protein Associated with Alzheimer Disease

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed lineage kinase-dependent JNK module and also establishes an interaction with beta-amyloid precursor protein that has been partially characterized. Here we show that, similarly to other proteins involved in various neurological diseases, JIP1 becomes hyperphosphorylated following activation of stress-activated and MAP kinases. By immobilized metal affinity chromatography and a combined microcapillary LC/MALDI-TOF/ESI-ion trap mass spectrometry approach, we identified 35 sites of mitotic phosphorylation within JIP1, among which eight were present within (Ser/Thr)-Pro sequence. This motif is modified by various kinases in aggregates of the microtubule-associated protein tau, which generates typical intraneuronal lesions occurring in Alzheimer disease. Most of the post-translational modifications found were located within the JNK, MAP kinase kinase, and RAC-alpha Ser/Thr protein kinase binding regions; no modifications occurred in protein Src homology 3 and phosphotyrosine interaction domains, which are essential for binding to kinesin, beta-amyloid precursor protein, and MAP kinase kinase kinase. Protein phosphorylation is known to affect stability and protein-protein interactions. Thus, the findings that JIP1 is extensively phosphorylated after activation of stress-activated and MAP kinases indicate that these signaling pathways might modulate JIP1 signaling by regulating its stability and association with some, but not all, interacting proteins