Biochemical Properties and Physiological Functions of pLG72: Twenty Years of Investigations

In 2002, the novel human gene G72 was associated with schizophrenia susceptibility. This gene encodes a small protein of 153 amino acids, named pLG72, which represents a rare case of primate-specific protein. In particular, the rs2391191 single nucleotide polymorphism (resulting in in the R30K substitution) was robustly associated to schizophrenia and bipolar disorder. In this review, we aim to summarize the results of 20 years of biochemical investigations on pLG72. The main known role of pLG72 is related to its ability to bind and inactivate the flavoenzyme d-amino acid oxidase, i.e., the enzyme that controls the catabolism of d-serine, the main NMDA receptor coagonist in the brain. pLG72 was proposed to target the cytosolic form of d-amino acid oxidase for degradation, preserving d-serine and protecting the cell from oxidative stress generated by hydrogen peroxide produced by the flavoenzyme reaction. Anyway, pLG72 seems to play additional roles, such as affecting mitochondrial functions. The level of pLG72 in the human body is still a controversial issue because of its low expression and challenging detection. Anyway, the intriguing hypothesis that pLG72 level in blood could represent a suitable marker of Alzheimer's disease progression (a suggestion not sufficiently established yet) merits further investigations

Behavioural multigenerational effect induced by the administration of very low doses of zinc during pregnancy, lactation and prepuberal period in the rat

In previous studies from this laboratory, the chronic administration of ZnTe during pregnancy, lactation and prepuberal stages of litters (F1 generation), the behavioural patterns of motivated exploration, lateralized exploration, social activity and survival responses of the maturing rats were modified. In order to find out if these affected behaviours should extend to the next generation, F1 litter rats, exposed previously to tellurium (Te) up to 30 days of age were left at rest with no further treatment up to reach 70 day-old. Then, F1 female rats were mated with normal untreated male rats, and in the next generation (F2), the litter rats at 30 day-old preserved the modified behaviours previously observed in their parents. This evidence suggested that Te effects were intergenerational. In the present work, considering that in the first study ZnTe was used, and it is well known that Zn ion has many physiological functions in the cell, experiments were done in order to define if Zn could have a similar intergenerational effect than Te. Working with the same experimental setup than in previous experiments, but using ZnCl2 instead of ZnTe, results shown that none of the behavioural responses studied were affected in F1 generation. However, in F2 generation lateralized exploration and survival behaviour were inhibited, suggesting that Zn also has an intergenerational effect.Fil: Ratti, Silvia Gabriela. Universidad Catolica de Cuyo. Sede San Luis. Facultad de Ciencias Medicas. Laboratorio de Epigenesis y Neuropsicofarmacologia Experimental; ArgentinaFil: Sacchi, Osvaldo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Alvarez, Edgardo Oscar. Universidad Catolica de Cuyo. Sede San Luis. Facultad de Ciencias Medicas. Laboratorio de Epigenesis y Neuropsicofarmacologia Experimental; Argentin

The inorganic chemicals that surround us: role of tellurium, selenium and zinc on behavioural functions in mammals

Living organisms live in continuous interaction with its environment.During this process changes in one can induce adaptive responses on theother. Many factors in the environment have been studied with thenotorious distinction of been rare or to be of high intensity strength in itsinteraction with living organisms. However, little attention has been puton some factors that have constant interaction with organisms butusually have low intensity strength, such as the case of the inorganicchemical environment that surrounds us. In this review, the interactionbetween the chemical element and living organisms is discussed under atheoretical model of interaction between compartments, giving attentionto tellurium (Te), zinc (Zn) and selenium (Se) on some cognitivefunctions in human and animals. After studies in our laboratory of thephenotypic expression of the HSR (Hand Skill Relative) gene in schoolchildren community living in geographic zone rich in minerals andmines of La Rioja province, Argentine, where Te was found to be inhigher non‐toxic concentrations, a translational experimental model tomaturing rats exposed to this trace element was made. Te was found toincrease some parameters related to locomotion in an open field inducedby novelty and exploratory motivation. At the same time, inhibition oflateralized responses, survival responses and social activity was alsoobserved. Some of these changes, particularly those related tolateralization had similarity with that found previously in children of LaRioja province. Discussion of similarities and discrepancies of biologiceffects between animals and humans, about the possible meaning of Teand its interaction with Zn and Se with relevance to humans wasanalyzed.Fil: Alvarez, Edgardo Oscar. Universidad Catolica de Cuyo. Sede San Luis. Facultad de Ciencias Medicas. Laboratorio de Epigenesis y Neuropsicofarmacologia Experimental; ArgentinaFil: Sacchi, Osvaldo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Catolica de Cuyo. Sede San Luis. Facultad de Ciencias Medicas. Laboratorio de Epigenesis y Neuropsicofarmacologia Experimental; ArgentinaFil: Ratti, Silvia Gabriela. Universidad Catolica de Cuyo. Sede San Luis. Facultad de Ciencias Medicas. Laboratorio de Epigenesis y Neuropsicofarmacologia Experimental; Argentin

The influence of Tellurium an Folic Acid Adminitration on Coping Behavioural Parameters in Maturing Rats: Transgenerational effects

A previous study of our laboratory have shown that Tellurium (Te), a metalloid with low concentrations in soil and water in the earth, is able to modify important behavioural parameters related to cognitive functions when administered orally in maturing rats. Exposition of chronic non-toxic doses of Te affected spontaneous lateralized exploration, social interaction behaviour, and survival responses in the treated rats. Te effects were blocked by the simultaneous administration of folic acid, a well-known methyl group donor in the cell, suggesting an epigenetic mode of action of Te. Te behavioural effects on the second generation (F1 ) still were found in the next third generation (F2 ). In order to evaluate if these transgenerational behavioural alterations in F2 were depending on DNA methylating mechanisms, as observed in the F1 generation, F1 rats were mated at 90 days of age. Two groups of animals in the F2 offspring were formed; one treated with and the other not treated with folic acid. Results showed that the untreated folic acid F2 maturing rats, conserved the same pattern of behavioural alterations than its parents (F1 ), in spite that they were not exposed to Te. Those F2 animals treated with folic acid, instead recovered the normal behavioural responses in the three tests performed to evaluate coping behaviour. Results suggest that the molecular mechanism of Te is dependent on DNA methylating reactions, which is one of the molecular processes of epigenetic modulation in mammalsFil: Ratti, Silvia Gabriela. Universidad Nacional de Cuyo; ArgentinaFil: Sacchi, Osvaldo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Alvarez, Edgardo O. Universidad Nacional de Cuyo; Argentin

Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level

Mechanisms of NMDA receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of NMDA receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the NMDAR glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of NMDARs at synapses in the amygdala under low-activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced NMDAR-mediated synaptic events, serving an essential function in the induction of NMDAR-dependent long-term potentiation in fear conditioning pathways

Breast cancer with choriocarcinomatous features

This report describes the case of a 45 year-old patient with breast carcinoma characterized by choriocarcinomatous features, presence of bizarre anaplastic cells with areas of necrosis and multinucleated giant cells. The immuno-histochemical analysis showed positivity for chromogranin and β-HCG. The tumor size was 5.7 cm at the largest axis and it was refractory to initial neo-adjuvant treatment. Mastectomy was performed and after microscopic and immuno-histochemical examination it was diagnosed as carcinoma with choriocarcinomatous features. These lesions are rare and liable to synthesize hormonal substances not specific to breast tissue. Its diagnosis is highly significant to the therapeutic and prognostic approach insofar as these lesions are potentially aggressive.O presente relato descreve um caso de carcinoma mamário em paciente de 45 anos, com diferenciação coriocarcinomatosa, caracterizado por presença de células bizarras, anaplásicas, com áreas de necrose e células gigantes multinucleadas, com imunopositividade para a subunidade β da gonadotrofina coriônica humana (β-HCG) e cromogranina, medindo 5,7 cm no maior eixo, refratário ao tratamento neoadjuvante inicial. Realizada mastectomia, cujo diagnóstico após análises microscópica e imuno-histoquímica concluiu tratar-se de carcinoma com características coriocarcinomatosas. Tais lesões são raras, capazes de sintetizar substâncias hormonais não próprias ao tecido mamário, sendo o diagnóstico de grande importância para a abordagem terapêutica e prognóstica, pois constituem um grupo de lesões potencialmente agressivas.Faculdade de Medicina do ABC Serviço de Patologia da MamaFMABCUniversidade Federal de São Paulo (UNIFESP)UNIFESPFMABC Laboratório de Análises ClínicasUNIFESP, EPM, São Paulo, BrazilSciEL

Socio-emotional and cognitive development in intrauterine growth restricted (IUGR) and typical development infants: Early interactive patterns and underlying neural correlates. Rationale and methods of the study

Intrauterine growth restriction (IUGR) is defined as a fetal growth retardation, resulting in an estimated fetal weight less than the 10th centile for gestational age. IUGR developing brain is affected by the atypical fetal growth, presenting altered structure and connectivity and increased risk for neurodevelopmental impairments. Behaviorally, IUGR infants show reduced responsiveness and engagement with human faces during mother-child exchanges. The neural mechanisms of these patterns of interactions remain unexplored, as well as their potential role in shaping socio-cognitive trajectories of development. Aim of this research project will be to longitudinally investigate mother-infant interactions and infant's event-related potential (ERP) components of face processing (infant N170, P400, Negative central) in 4 and 9 months IUGR as potential early markers of expected atypical cognitive and behavioral outcomes observed at 12 months. Thirty IUGR participants will be recruited after receiving the in utero diagnosis (>28th gestational week). Thirty healthy infants will be enrolled as the control group. Maternal environment will be assessed via Emotional Availability Scales (EASs), with child responsiveness and maternal sensitivity as variables of interest. Infants' scalp-recorded cortical activity in response to social and non-social stimuli will be investigated using a high-density EEG system (EGI Geodesic system). Neurodevelopment will be measured at 12 months of child's life, using Bayley Scales for Infant Development (BSID), while the possible presence of emotional-behavioral problems will be rated via Child Behavior Checklist (CBCL). We expect that being IUGR significantly affects cognitive and behavioral outcomes, through mediation effects of both infants' neural and behavioral capacity to respond to social stimuli. Indeed, we expect an altered response to social stimuli in IUGR infants, resulting in smaller ERP components amplitude in response to human faces compared to healthy matched peers. A significant association between neural response to social stimuli and infants' responsiveness to maternal stimulation during interactions is expected, with impoverished performances on the interactive domain in IUGR, compared to healthy peers. This study will enhance understanding on neural mechanisms underpinning the interactive patterns sustaining socio-cognitive development in IUGR and healthy infants. The study will help in clarifying the role of postnatal environment in buffering the vulnerability experienced by children delayed in their fetal growth

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium

Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection

Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies