C/EBPß Regulates TFAM Expression, Mitochondrial Function and Autophagy in Cellular Models of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein ß (C/EBPß) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPß was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPß overexpression increased TFAM promoter activity. However, downregulation of C/EBPß in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPß. Then, we concluded that C/EBPß is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions.

Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration.

Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we described a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging.Abbreviations : 4-HNE: 4-hydroxynonenal; AMBRA1: autophagy and beclin 1 regulator 1, AMD: age-related macular degeneration;; GCL: ganglion cell layer; GFAP: glial fibrillary acidic protein; GLUL: glutamine synthetase/glutamate-ammonia ligase; HCL: hierarchical clustering; INL: inner nuclear layer; IPL: inner plexiform layer; LC/GC-MS: liquid chromatography/gas chromatography-mass spectrometry; MA: middle-aged; MTDR: MitoTracker Deep Red; MFI: mean fluorescence intensity; NL: NH4Cl and leupeptin; Nqo: NAD(P)H quinone dehydrogenase; ONL: outer nuclear layer; OPL: outer plexiform layer; OP: oscillatory potentials; OXPHOS: oxidative phosphorylation; PCR: polymerase chain reaction; PRKC/PKCα: protein kinase C; POS: photoreceptor outer segment; RGC: retinal ganglion cells; RPE: retinal pigment epithelium; SI: sodium iodate; TCA: tricarboxylic acid.

¿Se puede humanizar el Servicio de Atención de Pacientes Críticos del Hospital El Cruce? / Is it possible to humanize the Critical Patient Care Service of El Cruce Hospital?

[RESUMEN]. Muchas instituciones sanitarias continúan con un enfoque del modelo biomédico centrando sus acciones en los procedimientos y no en la persona y en su integridad, propiciando la deshumanización de la atención y reduciendo lo humano a lo biológico. Este paradigma ha ido cambiando en el último tiempo. La Organización Mundial de la Salud, OMS define a la salud como: "un estado completo de bienestar físico, mental y social, y no solamente la ausencia de afecciones o enfermedades" (1). La atención humanizada de la salud se centra en la persona, como ser multidisciplinario y único respetando sus valores y su libertad de elección. Realizamos un estudio descriptivo y observacional basado en el registro de intervenciones del área de cuidados humanizados realizadas en el Servicio de Atención del paciente crítico, APC entre enero y septiembre de 2023. Las mismas fueron realizadas luego de la solicitud de interconsultas realizadas por los médicos tratantes del servicio de APC. Durante el período de estudio, se llevaron a cabo un total de 117 intervenciones que reflejan acciones concretas de cuidados humanizados. Estas incluyeron 34 intervenciones en comunicación efectiva, 29 acompañamientos familiares, 22 sesiones de soporte psicoespiritual, 16 tratamientos para el dolor, 11 adecuaciones del esfuerzo terapéutico, 4 cuidados integrales en etapas terminales de la vida y 1 seguimiento del duelo. Estos indicadores sugieren un avance hacia una atención más humanizada al reconocer y abordar las necesidades de pacientes y familias mediante una comunicación empática, lo cual refleja una búsqueda activa de mejora en la calidad de vida en momentos críticos.

[ABSTRACT]. Many health institutions continue with an approach to the biomedical model, focusing their actions on procedures and not on the person and their integrity, promoting the dehumanization of care and reducing the human to the biological. This paradigm has been changing in recent times. The World Health Organization defines health as: "a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity." Humanized health care focuses on the person, as a multidisciplinary and unique being, respecting their values and their freedom of choice. We carried out a descriptive and observational study based on the record of interventions in the humanized care area carried out in the APC between January and September 2023. They were carried out after the request for interconsultations carried out by the treating physicians of the APC service. During the study period, a total of 117 interventions were carried out that reflect concrete actions of humanized care. These included 34 interventions in effective communication, 29 family accompaniment, 22 psychospiritual support sessions, 16 pain treatments, 11 adaptations of the therapeutic effort, 4 comprehensive care in terminal stages of life and 1 grief follow-up. These indicators suggest progress towards more humanized care by recognizing and addressing the needs of patients and families through empathetic communication, which reflects an active search for improvement in quality of life in critical moments.

Importance of cardiac imaging assessment of epicardial adipose tissue after a first episode of myocardial infarction.

Background: Over the past years, information about the crosstalk between the epicardial adipose tissue (EAT) and the cardiovascular system has emerged. Notably, in the context of acute myocardial infarction (AMI), EAT might have a potential role in the pathophysiology of ventricular structural changes and function, and the clinical evolution of patients. This study aims to assess the impact of EAT on morpho-functional changes in the left ventricle (LV) and the outcome of patients after an AMI. Methods: We studied prospectively admitted patients to our hospital with a first episode of AMI. All patients underwent percutaneous coronary intervention (PCI) during admission. Transthoracic echocardiography (TTE) was performed within 24-48 h after PCI, as well as blood samples to assess levels of galectin-3 (Gal-3). Cardiac magnetic resonance (CMR) was performed 5-7 days after PCI. Clinical follow-up was performed at 1 and 5 years after MI. Results: Mean age of our cohort (n = 41) was 57.5 ± 10 years, and 38 (93%) were male. Nine patients had normal BMI, 15 had overweight (BMI 25-30), and 17 were obese (BMI > 30). Twenty three patients (56%) had ≥ 4 mm thickness of EAT measured with echo. In these patients, baseline left ventricular ejection fraction (LVEF) after AMI was significantly lower, as well as global longitudinal strain. EAT thickness ≥ 4 m patients presented larger infarct size, higher extracellular volume, and higher T1 times than patients with EAT < 4 mm. As for Gal-3, the median was 16.5 ng/mL [12.7-25.2]. At five-year follow-up 5 patients had major cardiac events, and all of them had EAT ≥ 4 mm. Conclusions: Patients with EAT >4 mm have worse LVEF and GLS, larger infarct size and longer T1 values after a MI, and higher levels of Gal-3. EAT >4 mm was an independent predictor of MACE at 5-year follow-up. EAT thickness is a feasible, noninvasive, low-cost parameter that might provide important information regarding the chronic inflammatory process in the myocardium after an infarction.

Neuroprotective and Anti-Inflammatory Effects of Linoleic Acid in Models of Parkinson's Disease: The Implication of Lipid Droplets and Lipophagy.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.

Exclusive circulation of canine parvovirus type 2c in the Guadalajara metropolitan area in western Mexico: a five-year study.

Canine parvovirus type 2 (CPV-2) infection in dogs is associated with severe gastroenteritis, bloody diarrhea, and vomiting, resulting in high rates of death, especially in unvaccinated puppies within the first months of age. There are three variants, called CPV-2a, CPV-2b, and CPV-2c, co-circulating worldwide. Our group previously reported that the only circulating CPV-2 variant in the Guadalajara metropolitan area in western Mexico was type 2c. Now, a five-year study was performed in order to investigate the possible dominance of CPV-2c in our region. Rectal swabs were collected from 146 dogs with clinical gastroenteritis from May 2014 to August 2019 at the Veterinary Hospital of the University of Guadalajara. Of these, 90 dogs tested positive for canine parvovirus by PCR. Most of the infected dogs with CPV-2 had a partial or incomplete vaccination status (n = 88, 97.8%). Approximately 65% (n = 59) of them were mixed-breed dogs, 77.8% (n = 70) were under 6 months of age, and 37.8% (n = 34) of them died from clinical complications. RFLP analysis of amplicons derived from the vp2 gene showed that all 90 DNA samples corresponded to CPV-2c, with no evidence of the presence of CPV-2a or CPV-2b variants. Twenty-nine of the 90 DNA samples were selected for amplification of a portion of the vp2 gene, and sequencing of these amplicons showed that all of them had the sequence GAA at codon 426, encoding the amino acid glutamic acid, which is characteristic of CPV-2c. Phylogenetic analysis showed that the CPV-2c sequences were related to those of viruses from Europe and South America. The present study indicates that CPV-2c is still the only variant circulating in the dog population of the Guadalajara metropolitan area.

The Future of Critical Care: Optimizing Technologies and a Learning Healthcare System to Potentiate a More Humanistic Approach to Critical Care.

While technological innovations are the invariable crux of speculation about the future of critical care, they cannot replace the clinician at the bedside. This article summarizes the work of the Society of Critical Care Medicine-appointed multiprofessional task for the Future of Critical Care. The Task Force notes that critical care practice will be transformed by novel technologies, integration of artificial intelligence decision support algorithms, and advances in seamless data operationalization across diverse healthcare systems and geographic regions and within federated datasets. Yet, new technologies will be relevant and meaningful only if they improve the very human endeavor of caring for someone who is critically ill.

N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo.

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Root Silicon Addition Induces Fe Deficiency in Cucumber Plants, but Facilitates Their Recovery After Fe Resupply. A Comparison With Si Foliar Sprays.

Silicon has not been cataloged as an essential element for higher plants. However, it has shown beneficial effects on many crops, especially under abiotic and biotic stresses. Silicon fertilization was evaluated for the first time on plants exposed to fluctuations in an Fe regime (Fe sufficiency followed by Fe deficiency and, in turn, by Fe resupply). Root and foliar Si applications were compared using cucumber plants that were hydroponically grown in a growth chamber under different Fe nutritional statuses and Si applied either to the roots or to the shoots. The SPAD index, Fe, and Mn concentration, ROS, total phenolic compounds, MDA concentration, phytohormone balance, and cell cycle were determined. The results obtained showed that the addition of Si to the roots induced an Fe shortage in plants grown under optimal or deficient Fe nutritional conditions, but this was not observed when Si was applied to the leaves. Plant recovery following Fe resupply was more effective in the Si-treated plants than in the untreated plants. A relationship between the ROS concentration, hormonal balance, and cell cycle under different Fe regimes and in the presence or absence of Si was also studied. The contribution of Si to this signaling pathway appears to be related more to the induction of Fe deficiency, than to any direct biochemical or metabolic processes. However, these roles could not be completely ruled out because several hormone differences could only be explained by the addition of Si.

Phosphodiesterase 7 Regulation in Cellular and Rodent Models of Parkinson's Disease.

Parkinson's disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3', 5'-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson's disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease. Here, we have used in vitro and in vivo models of Parkinson's disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.

Nutritional and meat quality characteristics of seven primal cuts from 9-month-old female veal calves: a preliminary study.

BACKGROUND: Beef is a highly nutritious and valuable food. In order to complete its nutritional information, this study determined the chemical and physicochemical parameters and fatty acid, amino acid and mineral contents in seven primal cuts from veal carcasses (shoulder clod (SC), inside round (IR), eye of round (ER), bottom round (BR), heel of round (HR), knuckle (KK) and tenderloin (TL)). RESULTS: The intramuscular fat content was higher and the cholesterol content was lower in TL than in the other cuts. The colour parameters also varied in the different primal cuts. The L* and b* values were highest in ER. Cooking losses were significantly (P < 0.001) affected by the cut of meat ranging from 20.85% in HR to 29.01% in ER. Determination of the shear force values permitted us to establish more tender muscle (TL with shear force 16.45 N cm-2 ) and less tender muscle (IR with shear force 47.27 N cm-2 ). The nutritional indices and fatty acid profile indicated that HR is the healthiest cut. All cuts evaluated provide important levels of dietary amino acids, although the contents of both essential and non-essential amino acids were highest in HR. Finally, K, Zn and Fe were affected by the type of veal cut. CONCLUSIONS: All primal cuts of veal provide important nutrients for human diets. The information of this research allows consumers to make healthful food choices, creating diets aimed at trying to correct deficiencies and providing objective data that differentiate between differently priced cuts of veal. © 2018 Society of Chemical Industry.

Silicon induced Fe deficiency affects Fe, Mn, Cu and Zn distribution in rice (Oryza sativa L.) growth in calcareous conditions.

A protective effect by silicon in the amelioration of iron chlorosis has recently been proved for Strategy 1 species, at acidic pH. However in calcareous conditions, the Si effect on Fe acquisition and distribution is still unknown. In this work, the effect of Si on Fe, Mn, Cu and Zn distribution was studied in rice (Strategy 2 species) under Fe sufficiency and deficiency. Plants (+Si or-Si) were grown initially with Fe, and then Fe was removed from the nutrient solution. The plants were then analysed using a combined approach including LA-ICP-MS images for each element of interest, the analysis of the Fe and Si concentration at different cell layers of root and leaf cross sections by SEM-EDX, and determining the apoplastic Fe, total micronutrient concentration and oxidative stress indexes. A different Si effect was observed depending on plant Fe status. Under Fe sufficiency, Si supply increased Fe root plaque formation, decreasing Fe concentration inside the root and increasing the oxidative stress in the plants. Therefore, Fe acquisition strategies were activated, and Fe translocation rate to the aerial parts was increased, even under an optimal Fe supply. Under Fe deficiency, +Si plants absorbed Fe from the plaque more rapidly than -Si plants, due to the previous activation of Fe deficiency strategies during the growing period (+Fe + Si). Higher Fe plaque formation due to Si supply during the growing period reduced Fe uptake and could activate Fe deficiency strategies in rice, making it more efficient against Fe chlorosis alterations. Silicon influenced Mn and Cu distribution in root.

CCAAT/Enhancer binding protein ß silencing mitigates glial activation and neurodegeneration in a rat model of Parkinson's disease.

The CCAAT/Enhancer binding protein ß (C/EBPß) is a transcription factor involved in numerous physiological as well as pathological conditions in the brain. However, little is known regarding its possible role in neurodegenerative disorders. We have previously shown that C/EBPß regulates the expression of genes involved in inflammatory processes and brain injury. Here, we have analyzed the effects of C/EBPß interference in dopaminergic cell death and glial activation in the 6-hydroxydopamine model of Parkinson's disease. Our results showed that lentivirus-mediated C/EBPß deprivation conferred marked in vitro and in vivo neuroprotection of dopaminergic cells concomitant with a significant attenuation of the level of the inflammatory response and glial activation. Additionally, C/EBPß interference diminished the induction of α-synuclein in the substantia nigra pars compacta of animals injected with 6-hydroxydopamine. Taking together, these results reveal an essential function for C/EBPß in the pathways leading to inflammatory-mediated brain damage and suggest novel roles for C/EBPß in neurodegenerative diseases, specifically in Parkinson's disease, opening the door for new therapeutic interventions.

The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro.

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.

Phosphodiesterase7 Inhibition Activates Adult Neurogenesis in Hippocampus and Subventricular Zone In Vitro and In Vivo.

The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling intracellular levels of cyclic adenosine 3',5'-monophosphate in the immune and central nervous system. We have previously shown that inhibitors of this enzyme are potent neuroprotective and anti-inflammatory agents. In addition, we also demonstrated that PDE7 inhibition induces endogenous neuroregenerative processes toward a dopaminergic phenotype. Here, we show that PDE7 inhibition controls stem cell expansion in the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the subventricular zone (SVZ) in the adult rat brain. Neurospheres cultures obtained from SGZ and SVZ of adult rats treated with PDE7 inhibitors presented an increased proliferation and neuronal differentiation compared to control cultures. PDE7 inhibitors treatment of neurospheres cultures also resulted in an increase of the levels of phosphorylated cAMP response element binding protein, suggesting that their effects were indeed mediated through the activation of the cAMP/PKA signaling pathway. In addition, adult rats orally treated with S14, a specific inhibitor of PDE7, presented elevated numbers of proliferating progenitor cells, and migrating precursors in the SGZ and the SVZ. Moreover, long-term treatment with this PDE7 inhibitor shows a significant increase in newly generated neurons in the olfactory bulb and the hippocampus. Also a better performance in memory tests was observed in S14 treated rats, suggesting a functional relevance for the S14-induced increase in SGZ neurogenesis. Taken together, our results indicate for the first time that inhibition of PDE7 directly regulates proliferation, migration and differentiation of neural stem cells, improving spatial learning and memory tasks. Stem Cells 2017;35:458-472.

Ferromagnetic bond of Li10 cluster: An alternative approach in terms of effective ferromagnetic sites.

In this work, a model to explain the unusual stability of atomic lithium clusters in their highest spin multiplicity is presented and used to describe the ferromagnetic bonding of high-spin Li10 and Li8 clusters. The model associates the (lack of-)fitness of Heisenberg Hamiltonian with the degree of (de-)localization of the valence electrons in the cluster. It is shown that a regular Heisenberg Hamiltonian with four coupling constants cannot fully explain the energy of the different spin states. However, a more simple model in which electrons are located not at the position of the nuclei but at the position of the attractors of the electron localization function succeeds in explaining the energy spectrum and, at the same time, explains the ferromagnetic bond found by Shaik using arguments of valence bond theory. In this way, two different points of view, one more often used in physics, the Heisenberg model, and the other in chemistry, valence bond, come to the same answer to explain those atypical bonds.

Using Perls Staining to Trace the Iron Uptake Pathway in Leaves of a Prunus Rootstock Treated with Iron Foliar Fertilizers.

The aim of this study was to trace the Fe uptake pathway in leaves of Prunus rootstock (GF 677; Prunus dulcis × Prunus persica) plants treated with foliar Fe compounds using the Perls blue method, which detects labile Fe pools. Young expanded leaves of Fe-deficient plants grown in nutrient solution were treated with Fe-compounds using a brush. Iron compounds used were the ferrous salt FeSO4, the ferric salts Fe2(SO4)3 and FeCl3, and the chelate Fe(III)-EDTA, all of them at concentrations of 9 mM Fe. Leaf Fe concentration increases were measured at 30, 60, 90 min, and 24 h, and 70 µm-thick leaf transversal sections were obtained with a vibrating microtome and stained with Perls blue. In vitro results show that the Perls blue method is a good tool to trace the Fe uptake pathway in leaves when using Fe salts, but is not sensitive enough when using synthetic Fe(III)-chelates such as Fe(III)-EDTA and Fe(III)-IDHA. Foliar Fe fertilization increased leaf Fe concentrations with all Fe compounds used, with inorganic Fe salts causing larger leaf Fe concentration increases than Fe(III)-EDTA. Results show that Perls blue stain appeared within 30 min in the stomatal areas, indicating that Fe applied as inorganic salts was taken up rapidly via stomata. In the case of using FeSO4 a progression of the stain was seen with time toward vascular areas in the leaf blade and the central vein, whereas in the case of Fe(III) salts the stain mainly remained in the stomatal areas. Perls stain was never observed in the mesophyll areas, possibly due to the low concentration of labile Fe pools.

Phosphodiesterase 7 inhibition induces dopaminergic neurogenesis in hemiparkinsonian rats.

UNLABELLED: Parkinson's disease is characterized by a loss of dopaminergic neurons in a specific brain region, the ventral midbrain. Parkinson's disease is diagnosed when approximately 50% of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) have degenerated and the others are already affected by the disease. Thus, it is conceivable that all therapeutic strategies, aimed at neuroprotection, start too late. Therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs with disease-modifying properties. In this regard, modulation of endogenous adult neurogenesis toward a dopaminergic phenotype might provide a new strategy to target Parkinson's disease by partially ameliorating the dopaminergic cell loss that occurs in this disorder. We have previously shown that a phosphodiesterase 7 (PDE7) inhibitor, S14, exerts potent neuroprotective and anti-inflammatory effects in different rodent models of Parkinson's disease, indicating that this compound could represent a novel therapeutic agent to stop the dopaminergic cell loss that occurs during the progression of the disease. In this report we show that, in addition to its neuroprotective effect, the PDE7 inhibitor S14 is also able to induce endogenous neuroregenerative processes toward a dopaminergic phenotype. We describe a population of actively dividing cells that give rise to new neurons in the SNpc of hemiparkinsonian rats after treatment with S14. In conclusion, our data identify S14 as a novel regulator of dopaminergic neuron generation. SIGNIFICANCE: Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the ventral midbrain. Currently, no cure and no effective disease-modifying therapy are available for Parkinson's disease; therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs for the treatment of this disorder. The present study reports that an inhibitor of the enzyme phosphodiesterase 7 (S14) induces proliferation in vitro and in vivo of neural stem cells, promoting its differentiation toward a dopaminergic phenotype and therefore enhancing dopaminergic neuron generation. Because this drug is also able to confer neuroprotection of these cells in animal models of Parkinson's disease, S14 holds great promise as a therapeutic new strategy for this disorder.

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential.

Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.

Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-tetrahydro-ß-carboline (Pinoline) and Melatonin-Pinoline Hybrids.

6-Methoxy-1,2,3,4-tetrahydro-ß-carboline (pinoline) and N-acetyl-5-methoxytryptamine (melatonin) are both structurally related to 5-hydroxytryptamine (serotonin). Here we describe the design, synthesis, and characterization of a series of melatonin rigid analogues resulting from the hybridization of both pinoline and melatonin structures. The pharmacological evaluation of melatonin-pinoline hybrids comprises serotonergic and melatonergic receptors, metabolic enzymes (monoamine oxidases), antioxidant potential, the in vitro blood-brain barrier permeability, and neurogenic studies. Pinoline at trace concentrations and 2-acetyl-6-methoxy-1,2,3,4-tetrahydro-ß-carboline (2) were able to stimulate early neurogenesis and neuronal maturation in an in vitro model of neural stem cells isolated from the adult rat subventricular zone. Such effects are presumably mediated via serotonergic and melatonergic stimulation, respectively.