Virus-Induced Epilepsy vs. Epilepsy Patients Acquiring Viral Infection: Unravelling the Complex Relationship for Precision Treatment.

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation's impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios.

Sources of Carotenoids in Amazonian Fruits.

Epidemiological studies have shown that a diet rich in bioactive components significantly reduces cardiovascular disease incidence and mortality. In this sense, there is a need for meta-analytical research that confirms this phenomenon and increases specific knowledge about certain bioactive compounds such as carotenoids. Thus, this systematic review and meta-analysis aim to disseminate knowledge about the sources of carotenoids in fruit consumed in the north of Brazil which are outside the Brazilian trade balance. A systematic review and a meta-analysis following the PRISMA guidelines were conducted based on a random effects synthesis of multivariable-adjusted relative risks (RRs). Searches of seven sources were carried out, including PubMed, Science Direct from Elsevier, Web of Science, Scielo, Eric Research and Google Scholar databases. The systematic review was guided by a systematic review protocol based on the POT strategy (population, outcome and type of study) adapted for use in this research. Mendeley was a resource used to organize and manage references and exclude duplicates of studies selected for review. In this review, we present the potential bioactive compounds concentrated in little-known fruit species from the Amazon and their benefits. Consuming fruits that are rich in notable constituents such as carotenoids is important for the prevention of chronic non-communicable diseases through anti-inflammatory and anticoagulant properties, as well as antivirals, immunomodulators and antioxidants agents that directly affect the immune response.

Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.

The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

Drosophila melanogaster as a model of systemic dermatophytosis.

BACKGROUND: Dermatophytosis is one of the most common fungal infections worldwide. The distribution of dermatophytes varies across continents, but the genera Trichophyton and Microsporum have emerged as the main isolated agents in humans and animals. OBJECTIVES: To validate Drosophila melanogaster flies as a fast and feasible model to study dermatophytic infections. METHODS: Wild-type (WT) and Toll-deficient D. melanogaster flies were infected by Trichophyton rubrum, T. mentagrophytes, Microsporum canis and Nannizzia gypsea by pricking with a needle previously dipped in inoculum concentrations ranging from 103 to 108 colony-forming units/mL. Establishment of infection was confirmed by survival curves, histopathological analysis and fungal burden. Thereafter, flies were treated with terbinafine, itraconazole and clioquinol. RESULTS: WT flies were predominantly resistant to the infection, whereas Toll-deficient flies succumbed to the four dermatophyte genera tested. The antifungal drugs protected flies from the infection, except for N. gypsea whose survival curves did not differ from the untreated group. CONCLUSIONS: This pilot study confirms that D. melanogaster is a suitable model to study the virulence and antifungal drug efficacy in dermatophyte species.

Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions.

This review investigates the intricate role of human endogenous retroviruses (HERVs) in cancer development and progression, explicitly focusing on HERV-K (HML-2). This paper sheds light on the latest research advancements and potential treatment strategies by examining the historical context of HERVs and their involvement in critical biological processes such as embryonic development, immune response, and disease progression. This review covers computational modeling for drug-target binding assessment, systems biology modeling for simulating HERV-K viral cargo dynamics, and using antiviral drugs to combat HERV-induced diseases. The findings presented in this review contribute to our understanding of HERV-mediated disease mechanisms and provide insights into future therapeutic approaches. They emphasize why HERV-K holds significant promise as a biomarker and a target.

Understanding Lamotrigine's Role in the CNS and Possible Future Evolution.

The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs to be determined. Recent studies have highlighted the involvement of LTG in modulating the activity of voltage-gated ion channels, particularly those related to the inhibition of neuronal excitability. Additionally, LTG has been found to have neuroprotective effects, potentially through the inhibition of glutamate release and the enhancement of GABAergic neurotransmission. LTG's unique mechanism of action compared to other anti-epileptic drugs has led to the investigation of its use in treating other CNS disorders, such as neuropathic pain, PTSD, and major depressive disorder. Furthermore, the drug has been combined with other anti-epileptic drugs and mood stabilizers, which may enhance its therapeutic effects. In conclusion, LTG's potential to modulate multiple neurotransmitters and ion channels in the CNS makes it a promising drug for treating various neurological disorders. As our understanding of its mechanism of action in the CNS continues to evolve, the potential for the drug to be used in new indications will also be explored.

Cobalt Ferrite Synthesized Using a Biogenic Sol-Gel Method for Biomedical Applications.

Cancer is one of the leading causes of death worldwide. Conventional treatments such as surgery, chemotherapy, and radiotherapy have limitations and severe side effects. Magnetic hyperthermia (MH) is an alternative method that can be used alone or in conjunction with chemotherapy or radiotherapy to treat cancer. Cobalt ferrite particles were synthesized using an innovative biogenic sol-gel method with powder of coconut water (PCW). The obtained powders were subjected to heat treatments between 500 °C and 1100 °C. Subsequently, they were characterized by thermal, structural, magnetic, and cytotoxic analyses to assess their suitability for MH applications. Through X-ray diffraction and Raman spectroscopy, it was possible to confirm the presence of the pure phase of CoFe2O4 in the sample treated at 1100 °C, exhibiting a saturation magnetization of 84 emu/g at 300 K and an average grain size of 542 nm. Furthermore, the sample treated at 1100 °C showed a specific absorption rate (SAR) of 3.91 W/g, and at concentrations equal to or below 5 mg/mL, is non-cytotoxic, being the most suitable for biomedical applications.

Improved Antioxidant and Mechanical Properties of Food Packaging Films Based on Chitosan/Deep Eutectic Solvent, Containing Açaí-Filled Microcapsules.

The development of biobased antioxidant active packaging has been valued by the food industry for complying with environmental and food waste concerns. In this work, physicochemical properties for chitosan composite films as a potential active food packaging were investigated. Chitosan films were prepared by solution casting, plasticized with a 1:2 choline chloride: glycerol mixture as a deep eutectic solvent (DES) and incorporated with 0-10% of optimized açaí oil polyelectrolyte complexes (PECs). Scanning electron microscopy and confocal laser scanning microscopy revealed that the chitosan composite films were continuous and contained well-dispersed PECs. The increased PECs content had significant influence on the thickness, water vapor permeability, crystallinity (CrD) and mechanical and dynamic behavior of the films, as well as their antioxidant properties. The tensile strength was reduced in the following order: 11.0 MPa (control film) > 0.74 MPa (5% DES) > 0.63 MPa (5% DES and 5% PECs). Films containing 2% of PECs had an increased CrD, ~6%, and the highest elongation at break, ~104%. Films with 1% of PECs displayed the highest antioxidant properties against the ABTS and DPPH radicals, ~6 and ~17 mg TE g-1, respectively, and highest equivalent polyphenols content (>0.5 mg GAE g-1). Films with 2% of particles were not significantly different. These results suggested that the chitosan films that incorporated 1-2% of microparticles had the best combined mechanical and antioxidant properties as a potential material for food packaging.

Polymeric Nanocapsules Containing Ozonated Oil and Terbinafine Hydrochloride as a Potential Treatment Against Dermatophytes.

Terbinafine hydrochloride is a synthetic allylamine whose mechanism of action consists of inhibiting the enzyme squalene epoxidase that participates in the first stage of ergosterol synthesis, interfering with fungal membrane function. Ozonated oils are used for topical application of ozone, producing reactive oxygen species that cause cellular damage in microorganisms, therefore being an alternative treatment for acute and chronic skin infections. This study aimed to develop and characterize Eudragit® RS100 nanocapsules, obtained by interfacial deposition of preformed polymer method, containing 0.5% terbinafine hydrochloride and 5% ozonated sunflower seed oil as a potential treatment against dermatophytes. The polymeric nanocapsules were characterized regarding particle size, zeta potential, pH, drug content, encapsulation efficiency, and stability. The in vitro drug release, in vitro skin permeation, and in vitro antifungal activity were also evaluated. The particle size was around 150 nm with a narrow size distribution, the zeta potential was around + 6 mV, and the pH was 2.2. The drug content was close to 95% with an encapsulation efficiency of 53%. The nanocapsules were capable to control the drug release and the skin permeation. The in vitro susceptibility test showed greater antifungal activity for the developed nanocapsules, against all dermatophyte strains tested, compared to the drug solution. Therefore, the polymeric nanocapsules suspension containing terbinafine hydrochloride and ozonated oil can be considered a potential high-efficacy candidate for the treatment of dermatophytosis, with a possible reduction in the drug dose and frequency of applications. Studies to evaluate safety and efficacy in vivo still need to be performed.

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.

BACKGROUND: Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. METHODS: Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. RESULTS: Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRASQ61K mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. CONCLUSIONS: Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.

Mutation m.3395A > G in MT-ND1 leads to variable pathologic manifestations.

A non-synonymous mtDNA mutation, m.3395A > G, which changes tyrosine in position 30 to cysteine in p.MT-ND1, was found in several patients with a wide range of clinical phenotypes such as deafness, diabetes and cerebellar syndrome but no Leber's hereditary optic neuropathy. Although this mutation has already been described, its pathogenicity has not been demonstrated. Here, it was found isolated for the first time, allowing a study to investigate its pathogenicity. To do so, we constructed cybrid cell lines and carried out a functional study to assess the possible consequences of the mutation on mitochondrial bioenergetics. Results obtained demonstrated that this mutation causes an important dysfunction of the mitochondrial respiratory chain with a decrease in both activity and quantity of complex I due to a diminution of p.MT-ND1 quantity. However, no subcomplexes were found in cybrids carrying the mutation, indicating that the quality of the complex I assembly is not affected. Moreover, based on the crystal structure of p.MT-ND1 and the data found in the literature, we propose a hypothesis for the mechanism of the degradation of p.MT-ND1. Our study provides new insights into the pathophysiology of mitochondrial diseases and in particular of MT-ND1 mutations.

Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity.

Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.

Relationship of behavioral inhibition to separation anxiety in a sample (N = 377) of adult individuals with mood and anxiety disorders.

BACKGROUND: Behavioral Inhibition (BI) is an early temperamental trait characterized by shyness, withdrawal, avoidance, uneasiness, and fear of unfamiliar situations, people, objects, and events. The DSM-5 refers to behavioral inhibition as a temperamental factor related to neurodevelopmental conditions in childhood, including attention deficit hyperactivity disorder, selective mutism, and specific phobias; and to its influence on adult anxiety disorders including social anxiety disorder, agoraphobia, and generalized anxiety disorder, but, interestingly, not separation anxiety disorder (SAD). However, there are phenomenological overlaps between BI and SAD. We aimed to explore whether there is a correlation between BI as an early temperamental trait and childhood or adult separation anxiety disorder. METHODS: The study was conducted in 377 consecutive adults (mean age 40.2±12.4 years) outpatients with anxiety and mood disorders as the principal diagnosis, grouped on the presence/absence of a DSM-5 diagnosis of childhood or adult separation anxiety disorder. Separation anxiety was assessed by the Structured Clinical Interview for Separation Anxiety (SCI-SAS) and the Adult Separation Anxiety Checklist (ASA27). Behavioral inhibition was assessed by the Retrospective Self-Report of Inhibition (RSRI). RESULTS: The four comparison groups included: 1) 168 patients without childhood or adult SAD, 2) 81 with adult SAD, 3) 97 with both adult SAD and childhood SAD, and 4) 31 with childhood SAD only. The group with both adult and childhood SAD had the highest scores on RSRI total and sub-scale scores. Both groups with adult SAD had significantly higher RSRI scores than the group with only childhood SAD or without SAD. Significant bivariate correlations were found between ASA-27 scores and RSRI scores. Correlations between RSRI scores and measures of anxiety and depressive symptoms were significantly weaker than those on the ASA-27. Regression analyses showed a significant predictive value of RSRI scores on ASA-27 total score, but not of age of onset of SAD. CONCLUSIONS: BI has an onset in the very first years of life and may represent a potential developmental endophenotype for later anxiety disorders. Our findings indicate that BI and separation anxiety are connected in individuals with affective and anxiety disorders. This may have important clinical and therapeutic implications for preventive interventions.

Fungicide Resistance in Fusarium graminearum Species Complex.

Fusariosis affects cereal grain crops worldwide and is responsible for devastating crops, reducing grain quality and yield, and producing strong mycotoxins. Benzimidazoles and triazoles were recommended to combat fusariosis; however, there were reports of resistance, making it necessary to reflect on the reasons for this occurrence. The purpose of this review was to evaluate the fusariosis resistance to the main agricultural fungicides, to observe whether this resistance can cause changes in the production of mycotoxins, and to verify the influence of resistance on the cereal grain production chain. Scientific articles were selected from the ScienceDirect, Scopus, and Pubmed databases, published at maximum 10 years ago and covering the main fungicide classes that combat phytopathogenesis and mycotoxin production. A high occurrence of resistance to carbendazim was found, while few reports of resistance to triazoles are available. The effectiveness of strobilurins is doubtful, due to an increase of mycotoxins linked to it. It is possible to conclude that the large-scale use of fungicides can select resistant strains that will contribute to an increase in the production of mycotoxins and harm sectors of the world economy, not only the agriculture, but also sanitation and foreign trade.

Drug Metabolism for the Identification of Clinical Biomarkers in Breast Cancer.

Breast cancer is classified into four major molecular subtypes, and is considered a heterogenous disease. The risk profiles and treatment of breast cancer differ according to these subtypes. Early detection dramatically improves the prospects of successful treatment, resulting in a reduction in overall mortality rates. However, almost 30% of women primarily diagnosed with the early-stage disease will eventually develop metastasis or resistance to chemotherapies. Immunotherapies are among the most promising cancer treatment options; however, long-term clinical benefit has only been observed in a small subset of responding patients. The current strategies for diagnosis and treatment rely heavily on histopathological examination and molecular diagnosis, disregarding the tumor microenvironment and microbiome involving cancer cells. In this review, we aim to praise the use of pharmacogenomics and pharmacomicrobiomics as a strategy to identify potential biomarkers for guiding and monitoring therapy in real-time. The finding of these biomarkers can be performed by studying the metabolism of drugs, more specifically, immunometabolism, and its relationship with the microbiome, without neglecting the information provided by genetics. A larger understanding of cancer biology has the potential to improve patient care, enable clinical decisions, and deliver personalized medicine.

Cannabidiol Antiproliferative Effect in Triple-Negative Breast Cancer MDA-MB-231 Cells Is Modulated by Its Physical State and by IGF-1.

Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has been discussed for its safety and efficacy in cancer treatments. For this reason, we have inquired into its use on triple-negative human breast cancer. Analyzing the biological effects of CBD on MDA-MB-231, we have demonstrated that both CBD dosage and serum concentrations in the culture medium influence its outcomes; furthermore, light scattering studies demonstrated that serum impacts the CBD aggregation state by acting as a surfactant agent. Pharmacological studies on CBD in combination with chemotherapeutic agents reveal that CBD possesses a protective action against the cytotoxic effect exerted by cisplatin on MDA-MB-231 grown in standard conditions. Furthermore, in a low serum condition (0.5%), starting from a threshold concentration (5 µM), CBD forms aggregates, exerts cytostatic antiproliferative outcomes, and promotes cell cycle arrest activating autophagy. At doses above the threshold, CBD exerts a highly cytotoxic effect inducing bubbling cell death. Finally, IGF-1 and EGF antagonize the antiproliferative effect of CBD protecting cells from harmful consequences of CBD aggregates. In conclusion, CBD effect is strongly associated with the physical state and concentration that reaches the treated cells, parameters not taken into account in most of the research papers.

Squarate Cross-Linked Gelatin Hydrogels as Three-Dimensional Scaffolds for Biomedical Applications.

Hydrogels are useful platforms as three-dimensional (3D) scaffolds for cell culture, drug-release systems, and regenerative medicine applications. Here, we propose a novel chemical cross-linking approach by the use of 3,4-diethoxy-3-cyclobutene-1,2-dione or diethyl squarate for the preparation of 5 and 10% w/v gelatin-based hydrogels. Hydrogels showed good swelling properties, and the 5% gelatin-based hydrogel proved suitable as a 3D cell culture scaffold for the chondrocyte cell line C28/I2. In addition, diffusion properties of different sized molecules inside the hydrogel were determined.

In vitro pharmacokinetics/pharmacodynamics modeling and efficacy against systemic candidiasis in Drosophila melanogaster of a bisaryloxypropanamine derivative.

The number of deaths due to systemic fungal infections is increasing alarmingly, which is aggravated by the limitations of traditional treatments and multidrug resistance. Therefore, the research and development of new therapeutic options against pathogenic fungi is an urgent need. To evaluate the fungicidal activity of a synthetic compound, 1,3-bis-(3,4-dichlorophenoxy)propan-2-aminium chloride (2j), through time-kill studies and pharmacokinetics/pharmacodynamics (PK/PD) modeling. The protective effect of the compound was also evaluated using the Drosophila melanogaster minihost model of candidiasis. Mathematical modeling of time-kill data of compound 2j was performed to obtain PD characteristics. Additionally, Toll-deficient D. melanogaster flies were infected with a Candida albicans strain and treated with 2j. We observed that compound 2j demonstrated a time- and dose-dependent fungicidal effect against Candida spp. and dermatophytes, even at low concentrations, and rapidly achieved kill rates reaching the maximum effect in less than one hour. The efficacy of the compound against systemic candidiasis in D. melanogaster flies was comparable to that achieved by fluconazole. These results support the potential of compound 2j as a systemic antifungal agent candidate and serve as a starting point for further studies involving mammalian animal models.

Evaluation of activity and toxicity of combining clioquinol with ciclopirox and terbinafine in alternative models of dermatophytosis.

Dermatophytosis is a superficial fungal infection that affects humans and is very common in small animals. The treatment using the most commonly used antifungals is failing, and new therapeutic alternatives are required to combat the resistance of these fungal infections. Previous studies by the group have shown that clioquinol is an important therapeutic alternative in the treatment of dermatophytosis. The object was to conduct studies of antidermatophytic activity and the irritant potential from the double and triple combinations of clioquinol, terbinafine and ciclopirox in ex vivo and in vivo alternative models. To evaluate the irritant potential of antifungal combinations, the alternative HET-CAM method (chicken egg test chorioallantoic membrane) was used. Ex vivo models were used to assess the effectiveness of antifungal combinations, using pig hooves and veterinary fur. Any possible tissue damage was to assess through in histopathology of swine ears. HET-CAM results showed that all combinations can be classified as non-irritating, corroborated by the results of the histopathological evaluation of the pig's ear skin. Only the double combinations managed to remove 100% of the colony-forming units (CFU) formed on the pig's hooves. The clioquinol + terbinafine combination and the triple combination were more effective than clioquinol + ciclopirox in eradicating the preformed biofilm in fur of veterinary origin. These results show the potential of formulations of clioquinol in combination with antifungals for use in humans and in the veterinary field to combat dermatophytosis, as an important alternative therapy, for use in the near future.

Carbonic anhydrase activation profile of indole-based derivatives.

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.