Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation.

Adult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.

Diversity and taxonomic revision of methanogens and other archaea in the intestinal tract of terrestrial arthropods.

Methane emission by terrestrial invertebrates is restricted to millipedes, termites, cockroaches, and scarab beetles. The arthropod-associated archaea known to date belong to the orders Methanobacteriales, Methanomassiliicoccales, Methanomicrobiales, and Methanosarcinales, and in a few cases also to non-methanogenic Nitrososphaerales and Bathyarchaeales. However, all major host groups are severely undersampled, and the taxonomy of existing lineages is not well developed. Full-length 16S rRNA gene sequences and genomes of arthropod-associated archaea are scarce, reference databases lack resolution, and the names of many taxa are either not validly published or under-classified and require revision. Here, we investigated the diversity of archaea in a wide range of methane-emitting arthropods, combining phylogenomic analysis of isolates and metagenome-assembled genomes (MAGs) with amplicon sequencing of full-length 16S rRNA genes. Our results allowed us to describe numerous new species in hitherto undescribed taxa among the orders Methanobacteriales (Methanacia, Methanarmilla, Methanobaculum, Methanobinarius, Methanocatella, Methanoflexus, Methanorudis, and Methanovirga, all gen. nova), Methanomicrobiales (Methanofilum and Methanorbis, both gen. nova), Methanosarcinales (Methanofrustulum and Methanolapillus, both gen. nova), Methanomassiliicoccales (Methanomethylophilaceae fam. nov., Methanarcanum, Methanogranum, Methanomethylophilus, Methanomicula, Methanoplasma, Methanoprimaticola, all gen. nova), and the new family Bathycorpusculaceae (Bathycorpusculum gen. nov.). Reclassification of amplicon libraries from this and previous studies using this new taxonomic framework revealed that arthropods harbor only CO2 and methyl-reducing hydrogenotrophic methanogens. Numerous genus-level lineages appear to be present exclusively in arthropods, suggesting long evolutionary trajectories with their termite, cockroach, and millipede hosts, and a radiation into various microhabitats and ecological niches provided by their digestive tracts (e.g., hindgut compartments, gut wall, or anaerobic protists). The distribution patterns among the different host groups are often complex, indicating a mixed mode of transmission and a parallel evolution of invertebrate and vertebrate-associated lineages.

A novel isolation method for spontaneously released extracellular vesicles from brain tissue and its implications for stress-driven brain pathology.

BACKGROUND: Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human biospecimens, especially in complex disorders in which pathological and specimen heterogeneity, as well as diverse individual clinical profile, often complicate the development of precision therapeutic schemes and patient-tailored treatments. Thus, the collection and characterization of physiologically relevant sEVs are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV fractions with intracellular vesicles. METHODS: Based on multiscale analytical platforms such as cryo-EM, label-free proteomics, advanced flow cytometry, and ExoView analyses, we compared and characterized the EV fraction isolated with this novel method with a classical digestion-based EV isolation procedure. Moreover, EV biogenesis was pharmacologically manipulated with either GW4869 or picrotoxin to assess the validity of the spontaneous-release method, while the injection of labelled-EVs into the mouse brain further supported the integrity of the isolated vesicles. RESULTS: We hereby present an efficient purification method that captures a sEV-enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated, as well as under animals' exposure to chronic stress, a clinically relevant precipitant of brain pathologies, such as depression and Alzheimer's disease. Our findings show that the released method monitors the drug-evoked inhibition or enhancement of sEVs secretion while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress-driven brain pathology. CONCLUSIONS: Overall, the spontaneous release method of sEV yield may contribute to the characterization and biomarker profile of physiologically relevant brain-derived sEVs in brain function and pathology. Video Abstract.

Menthol-based deep eutectic systems as antimicrobial and anti-inflammatory agents for wound healing.

Effective antimicrobial treatment has been identified as a serious and unmet medical need. Herein, we present a strategy based on deep eutectic systems (DES) to overcome current limitations, answering the need not only to effectively kill bacterial agents but also to avoid their adhesion and proliferation, which is associated with biofilm formation and have a crucial impact on bacterial virulence. To achieve such a goal, natural deep eutectic systems (NADES) based on menthol (Me) and saturated free fatty acids (FFA) were produced, fully physicochemical characterized, and its bioactive properties were described. The antimicrobial potential of menthol-based NADES with FFA, namely, myristic acid (MA), lauric acid (LA), and stearic acid (SA) were investigated towards a broad panel of microorganisms. The obtained data indicates that NADES possess effective antimicrobial properties towards the Gram-positive bacterial and fungal strains tested. Among the tested formulations, Me:LA at a molar ratio of 4:1 molar was used to carry out a biofilm detachment/removal assay due to is superior microbiological properties. This formulation was able to effectively lead to biofilm removal/dispersion of not only methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans, but also Escherichia coli, without the need of any additional physical force or antibiotic. Furthermore, since microbial invasion and biofilm formation is highly undesired in wound healing, namely in chronic wound healing, the wound healing properties of these eutectic formulations was also investigated. The results suggest that these NADES can cope with microbial invasion and biofilm detachment while not compromising normal keratinocyte proliferation and migration verified in wound healing and epidermis repair, while also contributing to the reduction of cell stress and inflammation via the control of ROS production. In conclusion, these results provide the indication that NADES based on Me and FFA holds great interest as antimicrobial agents for preventive and therapeutic applications in various clinical settings, including wound healing.

Chronic pain causes Tau-mediated hippocampal pathology and memory deficits.

Persistent pain has been recently suggested as a risk factor for dementia. Indeed, chronic pain is frequently accompanied by maladaptive brain plasticity and cognitive deficits whose molecular underpinnings are poorly understood. Despite the emerging role of Tau as a key regulator of neuronal plasticity and pathology in diverse brain disorders, the role of Tau has never been studied in the context of chronic pain. Using a peripheral (sciatic) neuropathy to model chronic pain in mice-spared nerve injury (SNI) for 4 months-in wildtype as well as P301L-Tau transgenic mice, we hereby demonstrate that SNI triggers AD-related neuropathology characterized by Tau hyperphosphorylation, accumulation, and aggregation in hippocampus followed by neuronal atrophy and memory deficits. Molecular analysis suggests that SNI inhibits autophagy and reduces levels of the Rab35, a regulator of Tau degradation while overexpression of Rab35 or treatment with the analgesic drug gabapentin reverted the above molecular changes leading to neurostructural and memory recovery. Interestingly, genetic ablation of Tau blocks the establishment of SNI-induced hippocampal morphofunctional deficits supporting the mediating role of Tau in SNI-evoked hippocampal pathology and memory impairment. These findings reveal that exposure to chronic pain triggers Tau-related neuropathology and may be relevant for understanding how chronic pain precipitates memory loss leading to dementia.

Comparing deep eutectic solvents and cyclodextrin complexes as curcumin vehicles for blue-light antimicrobial photodynamic therapy approaches.

Curcumin (Cur), a polyphenolic compound derived from Curcuma longa L., has garnered the attention of the scientific community due to its remarkable biological properties such as its potential as a photosensitizing agent for photodynamic therapy (PDT). However, due to its low solubility in aqueous media and instability at physiological and alkaline pH, Cur has struggled to find relevant clinical application. To tackle these shortcomings, two distinct Cur-based formulations based on either complexation with methyl-ß-cyclodextrin (MßCD), MßCDC-Cur, or dissolution in a choline chloride (ChCl): glycerol (Gly) deep eutectic solvent (DES), DES-Cur, were produced, physio-chemically characterized and compared regarding their potential as phototherapeutic agents for blue-light antimicrobial photodynamic therapy (aPDT) approaches. Both MßCD-Cur and DES-Cur were able to greatly enhance Cur solubility profile when compared to Cur powder. However, MßCD-Cur appears to hinder some of Cur's basal biological properties and possessed greater basal cytotoxicity towards L929 murine fibroblast cell line. Furthermore, MßCD-Cur was less photo-responsive when exposed to light which may hamper its application in blue-light aPDT approaches. In contrast, DES-Cur showed good biological properties and high photoresponsivity, displaying relevant phototoxicity against bacterial pathogens (≥ 99.9% bacterial reduction) while being better tolerated by L929 murine cells. Overall, this study found DES to be the more effective vehicle for Cur in terms of phototherapeutic potential which will serve as basis to develop novel platforms and approaches for blue-light aPDT targeting localized superficial infections.

Surface Functionalization of Ureteral Stents-Based Polyurethane: Engineering Antibacterial Coatings.

Bacterial colonization of polyurethane (PU) ureteral stents usually leads to severe and challenging clinical complications. As such, there is an increasing demand for an effective response to this unmet medical challenge. In this study, we offer a strategy based on the functionalization of PU stents with chitosan-fatty acid (CS-FA) derivatives to prevent bacterial colonization. Three different fatty acids (FAs), namely stearic acid (SA), oleic acid (OA), and linoleic acid (LinA), were successfully grafted onto chitosan (CS) polymeric chains. Afterwards, CS-FA derivatives-based solutions were coated on the surface of PU stents. The biological performance of the modified PU stents was evaluated against the L929 cell line, confirming negligible cytotoxicity of the developed coating formulations. The antibacterial potential of coated PU stents was also evaluated against several microorganisms. The obtained data indicate that the base material already presents an adequate performance against Staphylococcus aureus, which slightly improved with the coating. However, the performance of the PU stents against Gram-negative bacteria was markedly increased with the surface functionalization approach herein used. As a result, this study reveals the potential use of CS-FA derivatives for surface functionalization of ureteral PU stents and allows for conjecture on its successful application in other biomedical devices.

Accumulation of chemical elements and occurrence of microplastics in small pelagic fish from a neritic environment.

The assessment of contaminant exposure in marine organisms often focuses on the most toxic chemical elements from upper trophic level species. Information on mid-trophic level species and particularly on potentially less harmful elements is lacking. Additionally, microplastics have been considered emergent contaminants in aquatic environments which have not been extensively studied in species from mid-trophic levels in food chains. This study aims to contribute to an overall assessment of environmental impacts of such chemicals in a community of small pelagic fish in the North Atlantic. The concentrations of 16 chemical elements, rarely simultaneously quantified (including minerals, trace elements and heavy metals), and the presence of microplastics were analysed in sardines (Sardina pilchardus) and mackerels (Scomber spp. and Trachurus trachurus) sampled along the Portuguese coast. Biochemical stress assessments and stable isotope analyses were also performed. The chemical element concentrations in S. pilchardus, T. trachurus, and Scomber spp. were relatively low and lower than the levels reported for the same species in the North Atlantic and adjacent areas. No clear relationships were found between chemical elements and oxidative damage in fish. However, the concentration of several chemical elements showed differences among species, being related with the species' habitat use, trophic niches, and specific feeding strategies. The presence of plastic pieces in the stomachs of 29% of the sampled fishes is particularly concerning, as these small pelagic fish from mid-trophic levels compose a significant part of the diet of humans and other top predators. This study highlights the importance of multidisciplinary approaches focusing on the individual, including position data, stable isotopes, and oxidative stress biomarkers as complementary tools in contamination assessment of the marine mid-trophic levels in food chains.

A Fibrin Coating Method of Polypropylene Meshes Enables the Adhesion of Menstrual Blood-Derived Mesenchymal Stromal Cells: A New Delivery Strategy for Stem Cell-Based Therapies.

Polypropylene (PP) mesh is well-known as a gold standard of all prosthetic materials of choice for the reinforcement of soft tissues in case of hernia, organ prolapse, and urinary incontinence. The adverse effects that follow surgical mesh implantation remain an unmet medical challenge. Herein, it is outlined a new approach to allow viability and adhesion of human menstrual blood-derived mesenchymal stromal cells (MenSCs) on PP surgical meshes. A multilayered fibrin coating, based on fibrinogen and thrombin from a commercial fibrin sealant, was optimized to guarantee a homogeneous and stratified film on PP mesh. MenSCs were seeded on the optimized fibrin-coated meshes and their adhesion, viability, phenotype, gene expression, and immunomodulatory capacity were fully evaluated. This coating guaranteed MenSC viability, adhesion and did not trigger any change in their stemness and inflammatory profile. Additionally, MenSCs seeded on fibrin-coated meshes significantly decreased CD4+ and CD8+ T cell proliferation, compared to in vitro stimulated lymphocytes (p < 0.0001). Hence, the proposed fibrin coating for PP surgical meshes may allow the local administration of stromal cells and the reduction of the exacerbated inflammatory response following mesh implantation surgery. Reproducible and easy to adapt to other cell types, this method undoubtedly requires a multidisciplinary and translational approach to be improved for future clinical uses.

Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aß production.

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer's disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-ß (Aß) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aß overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, we show that Rab35 negatively regulates Aß production by sorting amyloid precursor protein (APP) and ß-secretase (BACE1) out of the endosomal network, where they interact to produce Aß. Interestingly, Rab35 coordinates distinct intracellular trafficking steps for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we demonstrate that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress-related and AD-related amyloidogenesis.

Where Dopaminergic and Cholinergic Systems Interact: A Gateway for Tuning Neurodegenerative Disorders.

Historically, many investigations into neurodegenerative diseases have focused on alterations in specific neuronal populations such as, for example, the loss of midbrain dopaminergic neurons in Parkinson's disease (PD) and loss of cholinergic transmission in Alzheimer's disease (AD). However, it has become increasingly clear that mammalian brain activities, from executive and motor functioning to memory and emotional responses, are strictly regulated by the integrity of multiple interdependent neuronal circuits. Among subcortical structures, the dopaminergic nigrostriatal and mesolimbic pathways as well as cholinergic innervation from basal forebrain and brainstem, play pivotal roles in orchestrating cognitive and non-cognitive symptoms in PD and AD. Understanding the functional interactions of these circuits and the consequent neurological changes that occur during degeneration provides new opportunities to understand the fundamental inter-workings of the human brain as well as develop new potential treatments for patients with dysfunctional neuronal circuits. Here, excerpted from a session of the European Behavioral Pharmacology Society meeting (Braga, Portugal, August 2019), we provide an update on our recent work in behavioral and cellular neuroscience that primarily focuses on interactions between cholinergic and dopaminergic systems in PD models, as well as stress in AD. These brief discussions include descriptions of (1) striatal cholinergic interneurons (CINs) and PD, (2) dopaminergic and cholinergic modulation of impulse control, and (3) the use of an implantable cell-based system for drug delivery directly the into brain and (4) the mechanisms through which day life stress, a risk factor for AD, damage protein and RNA homeostasis leading to AD neuronal malfunction.

Year-round element quantification of a wide-ranging seabird and their relationships with oxidative stress, trophic ecology, and foraging patterns.

Multidisciplinary approaches are essential to diligently assess environmental health status of ecosystems. In this study, year-round chemical elements' exposure and impacts were assessed on the wide-ranging Cory's shearwater Calonectris borealis breeding in Berlenga Island, offshore Portugal, North Atlantic Ocean. The aim was to identify potential contamination and oxidative stress sources associated with trophic ecology, habitat and spatial use, and foraging patterns. A set of 20 chemical elements were quantified, along with oxidative stress biomarkers, stable isotope analyses, and GPS tracking data. Birds presented higher accumulation to some non-essential elements along the year (i.e. arsenic, As; cadmium, Cd; mercury, Hg; lead, Pb; and strontium, Sr), in which concentrations were similar or surpassed other procellariform seabird populations all over the world. No significant differences were found for any of the elements between different periods within the breeding season, with exception of Hg. However, a Principal Component Analysis taking into consideration a group of elements showed differences between pre-laying and chick-rearing periods, with overall higher concentrations in the former. Individuals spending more time engaging in an intensive search for food, and in more coastal environments, presented overall higher element concentrations, and particularly Hg. Contrary to expectations, no relationships were found between chemical elements and oxidative stress. On the other hand, spatial use and foraging patterns of Cory's shearwaters influenced their oxidative stress responses. Our results highlight the need for multidisciplinary approaches to deepen understanding of the large-scale vulnerability of bioindicators such as seabirds and, by extension, the overall environmental health of ecosystems in which they rely.

Stable inheritance of Sinorhizobium meliloti cell growth polarity requires an FtsN-like protein and an amidase.

In Rhizobiales bacteria, such as Sinorhizobium meliloti, cell elongation takes place only at new cell poles, generated by cell division. Here, we show that the role of the FtsN-like protein RgsS in S. meliloti extends beyond cell division. RgsS contains a conserved SPOR domain known to bind amidase-processed peptidoglycan. This part of RgsS and peptidoglycan amidase AmiC are crucial for reliable selection of the new cell pole as cell elongation zone. Absence of these components increases mobility of RgsS molecules, as well as abnormal RgsS accumulation and positioning of the growth zone at the old cell pole in about one third of the cells. These cells with inverted growth polarity are able to complete the cell cycle but show partially impaired chromosome segregation. We propose that amidase-processed peptidoglycan provides a landmark for RgsS to generate cell polarity in unipolarly growing Rhizobiales.

Optimal Design of THEDES Based on Perillyl Alcohol and Ibuprofen.

Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical ingredients (APIs) bioavailability. However, their biological performance has not yet been carefully scrutinized. Herein, THEDES based on the binary mixture of perillyl alcohol (POH) and ibuprofen (IBU) were prepared using different molar ratios. Our comprehensive strategy includes the characterization of their thermal and structural behavior to identify the molar ratios that successfully form deep eutectic systems. The in vitro solubility of the different systems prepared has demonstrated that, unlike other reported examples, the presence of the terpene did not affect the solubility of the anti-inflammatory agent in a physiological simulated media. The biological performance of the systems was studied in terms of their antimicrobial activity against a wide panel of microorganisms. The examined THEDES showed relevant antimicrobial activity against all tested microbial strains, with the exception of P. aeruginosa. A synergistic effect from the combination of POH and IBU as a eutectic system was verified. Furthermore, the cytotoxic profile of these eutectic systems towards colorectal cancer (CRC) in vitro cell models was also evaluated. The results provide the indication that the cell viability varies in a dose-dependent manner, with a selective THEDES action towards CRC cells. With tunable bioactivities in a ratio-dependent manner, THEDES enhanced the antimicrobial and anticancer properties, representing a possible alternative to conventional therapies. Therefore, this study provides foreseeable indications about the utility of THEDES based on POH and IBU as strong candidates for novel active pharmaceutical systems.

Assessment of environmental health based on a complementary approach using metal quantification, oxidative stress and trophic ecology of two gull species (Larus michahellis & Larus audouinii) breeding in sympatry.

Metal pollution is currently a major issue in marine ecosystems, as organisms, and particularly seabirds, are exposed and accumulating increased levels from several anthropogenic sources. A set of 13 metals were quantified in two gull species breeding in sympatry, and in two distinct colonies separated by ca. 400 km. Oxidative stress was measured, and stable isotope analyses were used to link metal contamination and oxidative stress with the trophic ecology of each species/population. There was a clear segregation of metal contamination between the two species and to a much lesser extent between colonies. Overall, Audouin's gull was the most contaminated species for most metals, once this species relies mainly on fish and other marine resources. The Yellow-legged gull feeds regularly on terrestrial food sources besides fish, which may dilute contamination levels. Oxidative stress responses were related with birds' trophic ecology and foraging habitat, but apparently not with metal contamination.

Use of hemostatic agents for surgical bleeding in laparoscopic partial nephrectomy: Biomaterials perspective.

In recent years, there was an abrupt increase in the incidence of renal tumors, which prompt up the appearance of cutting-edge technology, including minimally invasive and organ-preserving approaches, such as laparoscopic partial nephrectomy (LPN). LPN is an innovative technique used to treat small renal masses that have been gaining popularity in the last few decades due to its promissory results. However, the bleeding control remains the main challenge since the majority of currently available hemostatic agents (HAs) used in other surgical specialities are inefficient in LPN. This hurried the search for effective HAs adapted for LPN surgical peculiarities, which resulted on the emergence of different types of topical HAs. The most promising are the natural origin HAs because of their inherent biodegradability, biocompatibility, and lowest toxicity. These properties turn them top interests' candidates as HAs in LPN. In this review, we present a deep overview on the progress achieved in the design of HAs based on natural origin polymers, highlighting their distinguishable characteristics and providing a clear understanding of their hemostat's role in LPN. This way it may be possible to establish a structure-composition properties relation, so that novel HAs for LPN can be designed to explore current unmet medical needs.

Correction: Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.

Deficits in decoding rewarding (and aversive) signals are present in several neuropsychiatric conditions such as depression and addiction, emphasising the importance of studying the underlying neural circuits in detail. One of the key regions of the reward circuit is the nucleus accumbens (NAc). The classical view on the field postulates that NAc dopamine receptor D1-expressing medium spiny neurons (D1-MSNs) convey reward signals, while dopamine receptor D2-expressing MSNs (D2-MSNs) encode aversion. Here, we show that both MSN subpopulations can drive reward and aversion, depending on their neuronal stimulation pattern. Brief D1- or D2-MSN optogenetic stimulation elicited positive reinforcement and enhanced cocaine conditioning. Conversely, prolonged activation induced aversion, and in the case of D2-MSNs, decreased cocaine conditioning. Brief stimulation was associated with increased ventral tegmenta area (VTA) dopaminergic tone either directly (for D1-MSNs) or indirectly via ventral pallidum (VP) (for D1- and D2-MSNs). Importantly, prolonged stimulation of either MSN subpopulation induced remarkably distinct electrophysiological effects in these target regions. We further show that blocking κ-opioid receptors in the VTA (but not in VP) abolishes the behavioral effects induced by D1-MSN prolonged stimulation. In turn, blocking δ-opioid receptors in the VP (but not in VTA) blocks the behavioral effects elicited by D2-MSN prolonged stimulation. Our findings demonstrate that D1- and D2-MSNs can bidirectionally control reward and aversion, explaining the existence of controversial studies in the field, and highlights that the proposed striatal functional opposition needs to be reconsidered.

Unveil the Anticancer Potential of Limomene Based Therapeutic Deep Eutectic Solvents.

Deep eutectic solvents have been recently reported as an interesting alternative to improve the therapeutic efficacy of conventional drugs, hence called therapeutic deep eutectic solvents (THEDES). The main objective of this work was to evaluate the potential of limonene (LIM) based THEDES as new possible systems for cancer treatment. LIM is known to have antitumor activity, however it is highly toxic and cell viability is often compromised, thus this compound is not selective towards cancer cells. Different THEDES based on LIM were developed to unravel the anticancer potential of such systems. THEDES were prepared by gently mixing saturated fatty acids menthol or ibuprofen (IBU) with LIM. Successful THEDES were obtained for Menthol:LIM (1:1), CA:LIM (1:1), IBU:LIM (1:4) and IBU:LIM(1:8). The results indicate that all the THEDES present antiproliferative properties, but IBU:LIM (1:4) was the only formulation able to inhibit HT29 proliferation without comprising cell viability. Therefore, IBU:LIM (1:4) was the formulation selected for further assessment of anticancer properties. The results suggest that the mechanism of action of LIM:IBU (1:4) is different from isolated IBU and LIM, which suggest the synergetic effect of DES. In this work, we unravel a methodology to tune the selectivity of LIM towards HT29 cell line without compromising cell viability of healthy cells. We demonstrate furthermore that coupling LIM with IBU leads also to an enhancement of the anti-inflammatory activity of IBU, which may be important in anti-cancer therapies.