Family adaptation in families of individuals with Down syndrome from 12 countries.

Our current understanding of adaptation in families of individuals with Down syndrome (DS) is based primarily on findings from studies focused on participants from a single country. Guided by the Resiliency Model of Family Stress, Adjustment, and Adaptation, the purpose of this cross-country investigation, which is part of a larger, mixed methods study, was twofold: (1) to compare family adaptation in 12 countries, and (2) to examine the relationships between family variables and family adaptation. The focus of this study is data collected in the 12 countries where at least 30 parents completed the survey. Descriptive statistics were generated, and mean family adaptation was modeled in terms of each predictor independently, controlling for an effect on covariates. A parsimonious composite model for mean family adaptation was adaptively generated. While there were cross-country differences, standardized family adaptation mean scores fell within the average range for all 12 countries. Key components of the guiding framework (i.e., family demands, family appraisal, family resources, and family problem-solving communication) were important predictors of family adaptation. More cross-country studies, as well as longitudinal studies, are needed to fully understand how culture and social determinants of health influence family adaptation in families of individuals with DS.

Induced-pluripotent stem cells and neuroproteomics as tools for studying neurodegeneration.

The investigation of neurodegenerative diseases advanced significantly with the advent of cell-reprogramming technology, leading to the creation of new models of human illness. These models, derived from induced pluripotent stem cells (iPSCs), facilitate the study of sporadic as well as hereditary diseases and provide a comprehensive understanding of the molecular mechanisms involved with neurodegeneration. Through proteomics, a quantitative tool capable of identifying thousands of proteins from small sample volumes, researchers have attempted to identify disease mechanisms by detecting differentially expressed proteins and proteoforms in disease models, biofluids, and postmortem brain tissue. The integration of these two technologies allows for the identification of novel pathological targets within the realm of neurodegenerative diseases. Here, we highlight studies from the past 5 years on the contributions of iPSCs within neuroproteomic investigations, which uncover the molecular mechanisms behind these illnesses.

Exploring the Pharmacognostical and Phytochemical Profiles of Aqueous Extracts of Kalanchoe.

The use of plants for medicinal purposes has a long history, however it is desirable a continuous evaluation seeking for complementary scientific evidences for their safe application. Species within the Kalanchoe genus are often referred to as "miracle leaf" due to their remarkable healing properties. Traditionally, these plants have been used to treat infections, inflammation, and cancer. Despite their widespread use, the identification of their active components remains incomplete. This study aimed to differentiate K. crenata (KC), K. marmorata (KM), and K. pinnata (KP) by conducting detailed histochemical and phytochemical analyses, and to assess their antioxidant capabilities. The investigation revealed significant differences between the species, highlighting the variability in phenolic (PC) and flavonoid contents (FC) and their distinct antioxidant effects. The KM demonstrated the greatest results (PC: 59.26±1.53 mgEqGA/g; FC: 12.63±0.91 mgEqCQ/g; DPPH⋅ (IC50): 110.66 ug/mL; ABTS⋅+ (IC50): 26.81 ug/mL; ORAC: 9.65±0.75 mmolTE) when compared to KC and KP. These findings underscore a new reference for research within the Kalanchoe genus.

The Healthy and Diseased Retina Seen through Neuron-Glia Interactions.

The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire that has been approached in the last decades in terms of signaling and diseases. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres and/or as organoids, are valuable to understand both neuronal and glial compartments, which have contributed to revealing roles and mechanisms between transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well as the recent transcriptome at the single cell level at different stages of development, also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions.

Oral care practices for patients in intensive care unit: A systematic review.

OBJECTIVES: To critically analyse and discuss oral hygiene protocols in the hospital environment in patients admitted to the ICU, through a systematic review of the literature. METHODS: The electronic search was performed on Pubmed, Cochrane, Web of Science and Google Scholar databases. The indexing keywords according to the PRISMA protocol were: 'hospital dentistry', 'oral health', 'oral care' and 'intensive care unit'. RESULTS: The initial search resulted in a total of 2671 articles. Pre-selection based on titles led to the exclusion of 2510 articles and the remaining 36 were selected for abstract reading. After analysing the eligibility of the articles, eight studies were included in the review and submitted to qualitative analysis. CONCLUSION: It can be concluded that cleaning with a soft bristle brush, use of chlorhexidine and lip moisturizing are methods commonly used in dental care actions in patients hospitalized in intensive care units.

Apoptosis in the neuroprotective effect of α7 nicotinic receptor in neurodegenerative models.

The α7 subtype of nicotinic receptors (α7 nAChRs) is one of the most abundant nicotinic receptor subtypes in the central nervous system (CNS) and both neurons and nonneuronal cells express α7 nAChRs. When activated, α7 nAChRs become permeable to cations and promote cellular responses such as anti-apoptotic signaling by modulating the caspases and proteins of the Bcl-2 family. Neuroprotection is an important function of these receptors, promoting neuronal survival under pathological conditions, including situations of stress and neuronal degeneration. Studies have demonstrated the relationship between the activation of these receptors and the reduction of neuronal or glial cell injury, by controlling apoptotic processes in different models, including neurodegenerative diseases such as Alzheimer's disease. Therefore, one of the most important signaling pathways activated by α7 nAChRs is the PI3K/Akt signaling cascade, which promotes the stimulation of anti-apoptotic molecules of the Bcl-2 family, Bcl-2 and Bcl-xl, and reduces the expression of caspases and proapoptotic molecules, resulting in cell survival. In Alzheimer's models, the literature shows that α7 nAChR activation attenuates Aß-induced neurotoxicity through modulation of different intrinsic apoptotic pathways via PI3K/Akt and mitogen-activated protein kinase (MAPK). In this review, we provide an up-to-date summary of the current evidence on the relationship between the activation of α7 nAChRs, a subtype of nicotinic acetylcholine receptor, and its role in neuroprotection by modulating apoptotic pathways.

Baru (Dipteryx alata Vog.) agro-industrial by-products promote the growth and metabolism of probiotic strains.

AIMS: To evaluate the phytochemical composition and effects of the baru peel and pulp (BPP) and the partially defatted baru nut (DBN) on the growth and metabolism of probiotics. METHODS AND RESULTS: The proximate composition, including dietary fibers, and polyphenol profile were determined in the BPP and DBN, and the prebiotic activity was evaluated on the growth and metabolism of the Lactobacillus and Bifidobacterium strains. BPP and DBN have a high content of insoluble fibers and phenolic compounds, mainly flavonoids and phenolic acids. Moreover, DBN stands out for its high content of proteins and lipids. BPP and DBN stimulated the growth and metabolism of Bifidobacterium animalis subsp. lactis BB-12, Lactobacillus acidophilus LA-05, and Lacticaseibacillus casei L-26. CONCLUSIONS: Baru by-products have potential prebiotic properties to be confirmed in preclinical and clinical studies, and to be explored as an ingredient in new health-promoting foods. IMPACT STATEMENT: Agro-industrial baru wastes, the peel plus pulp and the partially defatted nut, are sources of health-promoting compounds and stimulate the growth and metabolism of probiotics, indicating prebiotic properties.

Synthesis, characterization, antioxidant and antiparasitic activities new naphthyl-thiazole derivatives.

In this work, 13 thiosemicarbazones (1a - m) and 16 thiazoles (2a - p) were obtained, which were properly characterized by spectroscopic and spectrometric techniques. The pharmacokinetic properties obtained in silico revealed that the derivatives are in accordance with the parameters established by lipinski and veber, showing that such compounds have good bioavailability or permeability when administered orally. In assays of antioxidant activity, thiosemicarbazones showed moderate to high antioxidant potential when compared to thiazoles. In addition, they were able to interact with albumin and DNA. Screening assays to assess the toxicity of compounds to mammalian cells revealed that thiosemicarbazones were less toxic when compared to thiazoles. In relation to in vitro antiparasitic activity, thiosemicarbazones and thiazoles showed cytotoxic potential against the parasites Leishmania amazonensis and Trypanosoma cruzi. Among the compounds, 1b, 1j and 2l stood out, showing inhibition potential for the amastigote forms of the two parasites. As for the in vitro antimalarial activity, thiosemicarbazones did not inhibit Plasmodium falciparum growth. In contrast, thiazoles promoted growth inhibition. This study shows in a preliminary way that the synthesized compounds have antiparasitic potential in vitro.

Interleukin-4 activates divergent cell-intrinsic signals to regulate retinal cell proliferation induced by classical growth factors.

In the developing retina, precise coordination of cell proliferation, differentiation, and survival is essential for proper retinal maturation and function. We have previously reported evidence that interleukin-4 (IL-4) plays critical roles in neuronal differentiation and survival during retinal development. However, little is known about the role of IL-4 on retinal cell proliferation. In the current study, we investigated if IL-4 regulates cell proliferation induced by epidermal growth factor (EGF) and by fibroblast growth factor 2 (FGF2) in primary retinal cell cultures obtained from newborn rats. First, we show that EGF and FGF2 act as mitogens for glial cells, increasing proliferation of these cells in the retina. EGF- and FGF2-induced mitogenesis requires activation of distinct cell-intrinsic signals. In retinal cells exposed to FGF2, IL-4 downregulates p53 levels (a protein whose activation induces cell-cycle arrest) and increases mitogenic responsiveness to FGF2 through activation of protein kinase A (PKA) pathway. Conversely, in retinal cells exposed to EGF, IL-4 downregulates cyclin D1 levels (a protein required for cell-cycle progression), upregulates p53 levels, and decreases mitogenic responsiveness to EGF. The inhibitory effect induced by IL-4 on retinal cells exposed to EGF requires activation of Janus kinase 3 (JAK3), but not activation of PKA. Based on previous and current findings, we propose that IL-4 serves as a node of signal divergence, modulating multiple cell-intrinsic signals (e.g., cyclin D1, p53, JAK3, and PKA) and mitogenic responsiveness to cell-extrinsic signals (e.g., FGF2 and EGF) to control cell proliferation, differentiation, and survival during retinal development.

Synthesis of 4-(4-chlorophenyl)thiazole compounds: in silico and in vitro evaluations as leishmanicidal and trypanocidal agents.

Neglected tropical diseases are a diverse group of communicable pathologies that mainly prevail in tropical and subtropical regions. Thus, the objective of this work was to evaluate the biological potential of eight 4-(4-chlorophenyl)thiazole compounds. Tests were carried out in silico to evaluate the pharmacokinetic properties, the antioxidant, cytotoxic activities in animal cells and antiparasitic activities were evaluated against the different forms of Leishmania amazonensis and Trypanosoma cruzi in vitro. The in silico study showed that the evaluated compounds showed good oral availability. In a preliminary in vitro study, the compounds showed moderate to low antioxidant activity. Cytotoxicity assays show that the compounds showed moderate to low toxicity. In relation to leishmanicidal activity, the compounds presented IC50 values that ranged from 19.86 to 200 µM for the promastigote form, while for the amastigote forms, IC50 ranged from 101 to more than 200 µM. The compounds showed better results against the forms of T. cruzi with IC50 ranging from 1.67 to 100 µM for the trypomastigote form and 1.96 to values greater than 200 µM for the amastigote form. This study showed that thiazole compounds can be used as future antiparasitic agents.

Different nutritional systems influence the tenderness and lipid oxidation of ewe lamb meat without altering gene expression.

Feeding is a determining factor in the various characteristics of sheep meat and animal performance, the objectives were to evaluate the effect of supplementation of ewe lambs finished in different nutritional planes on the gene expression of CASP3, CAPN1, CAPN2 and CAST and its possible association with meat quality. Samples of the Longissimus lumborum muscle of 24 ewe lambs were used, distributed in 3 groups (n=8): P (pasture), PS (pasture and supplement) and F (feedlot). Physicochemical analyses were performed for centesimal analysis, pH, lipid oxidation, Warner-Bratzler shear force and RT-qPCR for the analysis of relative gene expression of the following genes: CASP3, CAPN1, CAPN2 and CAST. There is an increase in daily weight gain and ethereal extract values in the meat of confined animals, due to the greater energy intake in the nutrition of these animals. Animals kept only on pasture have lower lipid oxidation in meat than other treatments because of the lower percentage of lipids. The Warner-Bratzler shear force is considerably higher in the meat of animals kept only on pasture but is still considered tender. The different nutritional systems do not interfere with the gene expression of CASP3, CAPN1, CAPN2 and CAST in ewe lambs.

Highly Luminescent Europium(III) Complexes in Solution and PMMA-Doped Films for Bright Red Electroluminescent Devices.

This paper reports the synthesis, structure, photophysical, and optoelectronic properties of five eight-coordinate Europium(III) ternary complexes, namely, [Eu(hth)3(L)2], bearing 4,4,5,5,6,6,6-heptafluoro-1-(2-thienyl)-1,3-hexanedione (hth) as a sensitizer and L = H2O (1), dpso (diphenyl sulphoxide, 2), dpsoCH3 (4,4'-dimethyl diphenyl sulfoxide, 3), dpsoCl (bis(4-chlorophenyl)sulphoxide, 4), and tppo (triphenylphosphine oxide, 5) as co-ligands. The NMR and the crystal structure analysis confirmed the eight-coordinate structures of the complexes in solution and in a solid state. Upon UV-excitation on the absorption band of the ß-diketonate ligand hth, all complexes showed the characteristic bright red luminescence of the Europium ion. The tppo derivative (5) displayed the highest quantum yield (up to 66%). As a result, an organic light-emitting device, OLED, was fabricated with a multi-layered structure-ITO/MoO3/mCP/SF3PO:[complex 5] (10%)/TPBi:[complex 5] (10%)/TmPyPB/LiF/Al-using complex 5 as the emitting component.

Ouabain-Na+/K+-ATPase Signaling Regulates Retinal Neuroinflammation and ROS Production Preventing Neuronal Death by an Autophagy-Dependent Mechanism Following Optic Nerve Axotomy In Vitro.

Ouabain is a classic Na+K+ATPase ligand and it has been described to have neuroprotective effects on neurons and glial cells at nanomolar concentrations. In the present work, the neuroprotective and immunomodulatory potential of ouabain was evaluated in neonatal rat retinal cells using an optic nerve axotomy model in vitro. After axotomy, cultured retinal cells were treated with ouabain (3 nM) at different periods. The levels of important inflammatory receptors in the retina such as TNFR1/2, TLR4, and CD14 were analyzed. We observed that TNFR1, TLR4, and CD14 were decreased in all tested periods (15 min, 45 min, 24 h, and 48 h). On the other hand, TNFR2 was increased after 24 h, suggesting an anti-inflammatory potential for ouabain. Moreover, we showed that ouabain also decreased Iba-1 (microglial marker) density. Subsequently, analyses of retrograde labeling of retinal ganglion cells (RGC) were performed after 48 h and showed that ouabain-induced RGC survival depends on autophagy. Using an autophagy inhibitor (3-methyladenine), we observed a complete blockage of the ouabain effect. Western blot analyses showed that ouabain increases the levels of autophagy proteins (LC3 and Beclin-1) coupled to p-CREB transcription factor and leads to autophagosome formation. Additionally, we found that the ratio of cleaved/pro-caspase-3 did not change after ouabain treatment; however, p-JNK density was enhanced. Also, ouabain decreased reactive oxygen species production immediately after axotomy. Taken together, our results suggest that ouabain controls neuroinflammation in the retina following optic nerve axotomy and promotes RGC neuroprotection through activation of the autophagy pathway.

The endocannabinoid system and drug-associated contextual memories.

Drug abuse and addiction can be initiated and reinstated by contextual stimuli previously paired with the drug use. The influence exerted by the context on drug-seeking behaviour can be modelled in experimental animals with place-conditioning protocols. Here, we review the effects of cannabinoids in place conditioning and the therapeutic potential of the endocannabinoid system for interfering with drug-related memories. The phytocannabinoid Δ9-tetrahydrocannabinol (THC) tends to induce conditioned place preference (CPP) at low doses and conditioned place aversion at high doses; cannabidiol is devoid of any effect, yet it inhibits CPP induced by some drugs. Synthetic CB1 receptor agonists tend to recapitulate the biphasic profile observed with THC, whereas selective antagonists/inverse agonists inhibit CPP induced by cocaine, nicotine, alcohol and opioids. However, their therapeutic use is limited by potential psychiatric side effects. The CB2 receptor has also attracted attention, because selective CB2 receptor agonists inhibit cocaine-induced CPP. Inhibitors of endocannabinoid membrane transport and hydrolysis yield mixed results. In targeting the endocannabinoid system for developing new treatments for drug addiction, future research should focus on 'neutral' CB1 receptor antagonists and CB2 receptor agonists. Such compounds may offer a well-tolerated pharmacological profile and curb addiction by preventing drug-seeking triggered by conditioned contextual cues.

Ultrathin CAD-CAM glass-ceramic and composite resin occlusal veneers for the treatment of severe dental erosion: An up to 3-year randomized clinical trial.

STATEMENT OF PROBLEM: Ultrathin bonded posterior occlusal veneers represent a conservative alternative to traditional onlays and complete coverage crowns for the treatment of erosive dental wear. Data regarding the clinical performance of ceramic and composite resin ultrathin occlusal veneers are lacking. PURPOSE: The purpose of this prospective randomized clinical trial was to evaluate the influence of computer-aided design and computer-aided manufacturing (CAD-CAM) restorative material (ceramic versus composite resin) on the clinical performance of ultrathin occlusal veneers bonded to worn posterior teeth. MATERIAL AND METHODS: Eleven participants (mean age, 30.4 years) had their posterior teeth restored with 24 ceramic (e.max CAD) and 36 composite resin (Lava Ultimate) ultrathin occlusal veneers. The material type was assigned randomly. The tooth preparations were trial restoration driven and included immediate dentin sealing (OptiBond FL). The intaglio surfaces of the ceramic restorations were etched with hydrofluoric acid and silanated, and the composite resins were airborne-particle abraded and silanated. The tooth preparations were airborne-particle abraded and etched with phosphoric acid before restoration insertion. All restorations were adhesively luted with preheated composite resin (Filtek Z100). The participants were evaluated according to the modified United States Public Health Service (USPHS) criteria at baseline and then each year for up to 3 years. Survival rates were estimated with time to failure (primary outcome of interest) as the endpoint (scores 4 or 5). RESULTS: No restorations were lost. Five partial failures, in the form of chipping (all scored 4), were observed in the composite resin group (Lava Ultimate). The Kaplan-Meier survival rates were 100% for ceramic and 84.7% (SE 0.065%) for composite resin. Differences between the 2 groups were not statistically significant (P=.124). In the surviving restorations, significant difference (P=.003) was found for surface roughness as restorations in the composite resin group experienced some surface degradation. CONCLUSIONS: The findings of this medium-term clinical trial suggest that ceramic (e.max CAD) and composite resin (Lava Ultimate) CAD-CAM ultrathin occlusal veneers presented statistically comparable performance regardless of the minor partial failures (restorable chipping) observed in the composite resin group. Higher surface degradation was observed in the composite resin group.

Curcumin and n-acetylcysteine cocrystal produced with supercritical solvent: characterization, solubility, and preclinical evaluation of antinociceptive and anti-inflammatory activities.

Curcumin presents a promising anti-inflammatory potential, but its low water-solubility and bioavailability hinder its application. In this sense, cocrystallization represents a tool for improving physicochemical properties, solubility, permeability, and bioavailability of new drug candidates. Thus, the aim of this work was to produce curcumin cocrystals (with n-acetylcysteine as coformer, which possesses anti-inflammatory and antioxidant activities), by the anti-solvent gas technique using supercritical carbon dioxide, and to test its antinociceptive and anti-inflammatory potential. The cocrystal was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. The cocrystal solubility and antichemotaxic activity were also assessed in vitro. Antinociceptive and anti-inflammatory activities were carried out in vivo using the acetic acid-induced abdominal writhing and carrageenan-induced paw oedema assays in mice. The results demonstrated the formation of a new crystalline structure, thereby confirming the successful formation of the cocrystal. The higher solubility of the cocrystal compared to pure curcumin was verified in acidic and neutral pH, and the cocrystal inhibited the chemotaxis of neutrophils in vitro. In vivo assays showed that cocrystal presents increased antinociceptive and anti-inflammatory potency when compared to pure curcumin, which could be related to an improvement in its bioavailability.

Machine learning algorithms for soybean yield forecasting in the Brazilian Cerrado.

BACKGROUND: We evaluated different machine learning (ML) models for predicting soybean productivity up to 1 month in advance for the Matopiba agricultural frontier (States of Maranhão, Tocantins, Piauí, and Bahia). We collected meteorological data on the NASA-POWER platform and soybean yield on the SIDRA/IBGE base between 2008 and 2017. The ML models evaluated were random forest (RF), artificial neural networks, radial base support vector machines (SVM_RBF), linear model and polynomial regression. To assess the performance of the models, cross-validation was used, obtaining the value of precision by R2 , accuracy by root mean square error (RMSE), and trend by the mean error of the estimate (EME). RESULTS: The results showed that the RF algorithm achieves the highest precision and accuracy, with R2 of 0.81, RMSE of 176.93 kg ha-1 and trend (EME) of 1.99 kg ha-1 . On the other hand, the SVM_RBF algorithm showed the lowest performance, with R2 of 0.74, RMSE of 213.58 kg ha-1 and EME of -15.06 kg ha-1 . The average yield values predicted by the models were within the expected range for the region, which has a historical average value of 2.730 kg ha-1 . CONCLUSION: All models had acceptable precision, accuracy and trend indices, which makes it possible to use all algorithms to be applied in the prediction of soybean crop yield, observing the particularities of the region to be studied, in addition to being a useful tool for agricultural planning and decision making in soy-producing regions such as the Brazilian Cerrado. © 2021 Society of Chemical Industry.

Ultrasound-Guided Minimally Invasive Tissue Sampling: A Minimally Invasive Autopsy Strategy During the COVID-19 Pandemic in Brazil, 2020.

BACKGROUND: Minimally invasive autopsies, also known as minimally invasive tissue sampling (MITS), have proven to be an alternative to complete diagnostic autopsies (CDAs) in places or situations where this procedure cannot be performed. During the coronavirus disease 2019 (COVID-19) pandemic, CDAs were suspended by March 2020 in Brazil to reduce biohazard. To contribute to the understanding of COVID-19 pathology, we have conducted ultrasound (US)-guided MITS as a strategy. METHODS: This case series study includes 80 autopsies performed in patients with COVID-19 confirmed by laboratorial tests. Different organs were sampled using a standardized MITS protocol. Tissues were submitted to histopathological analysis as well as immunohistochemical and molecular analysis and electron microscopy in selected cases. RESULTS: US-guided MITS proved to be a safe and highly accurate procedure; none of the personnel were infected, and accuracy ranged from 69.1% for kidney, up to 90.1% for lungs, and reaching 98.7% and 97.5% for liver and heart, respectively. US-guided MITS provided a systemic view of the disease, describing the most common pathological findings and identifying viral and other infectious agents using ancillary techniques, and also allowed COVID-19 diagnosis confirmation in 5% of the cases that were negative in premortem and postmortem nasopharyngeal/oropharyngeal swab real-time reverse-transcription polymerase chain reaction. CONCLUSIONS: Our data showed that US-guided MITS has the capacity similar to CDA not only to identify but also to characterize emergent diseases.

Anti-angiogenic activity of azathioprine.

Azathioprine (AZA) is the main drug used in immunomodulatory therapy in post-transplant patients or with autoimmune diseases. However, no study has evaluated the AZA angiogenic response. Therefore, this study investigated the effects of AZA on the angiogenic process through macroscopic, histological, and immunohistochemical analyses in chick embryo chorioallantoic membrane (CAM). Our results showed potent anti-angiogenic activity of AZA at the higher concentrations tested in the CAM assay. The histological analysis of CAM confirmed this effect, since AZA induced a significant reduction in all parameters evaluated. In addition, immunohistochemical evaluation of CAM revealed that AZA decreased TGF-ß and VEGF levels, important cytokines involved in the angiogenic process. Therefore, the AZA anti-angiogenic effect identified in our study provides new information for the possible application of this drug in anticancer treatment.

Increased Retinal Ganglion Cell Survival by Exogenous IL-2 Depends on IL-10, Dopamine D1 Receptors, and Classical IL-2/IL-2R Signaling Pathways.

Interleukin-2 (IL-2) is a classical pro-inflammatory cytokine known to display neuroprotective roles in the central nervous system including the retina. In the present study, we investigate the molecular targets involved in the neurotrophic effect of IL-2 on retinal ganglion cells (RGC) after optic nerve axotomy. Analysis of retrograde labeling of RGC showed that common cell survival mediators, as Trk receptors, Src, PI3K, PKC, and intracellular calcium do not mediate the neurotrophic effect of IL-2 on RGC. No involvement of MAPK p38 was also observed. However, other MAPKs as MEK and JNK appear to be mediating this IL-2 effect. Our data also indicate that JAK2/3 are important intracellular proteins for the IL-2 effect. Interestingly, we demonstrate that the IL-2 effect depends on dopamine D1 receptors (D1R), the cAMP/PKA pathway, interleukin-10 (IL-10), and NF-κB, suggesting that RGC survival induced by IL-2 encompasses a molecular network of major complexity. In addition, treatment of retinal cells with recombinant IL-10 or 6-Cl-pb (D1R full agonist) was able to increase RGC survival similar to IL-2. Taken together, our results suggest that after optic nerve axotomy, the increase in RGC survival triggered by IL-2 is mediated by IL-10 and D1R along with the intracellular pathways of MAPKs, JAK/STAT, and cAMP/PKA.