Calcium signaling in prostate cancer cells of increasing malignancy

Abstract Calcium signaling controls a large variety of cell functions, including proliferation and apoptosis, and plays a major role in neoplastic transformation. Prostate cancer (PCa) is one of the most common malignancies in men. The transition to castration-resistant prostate cancer (CRPC), a lethal form that is still lacking an effective cure, could be influenced by fine tuning intracellular calcium ([Ca2+]i) homeostasis. This study investigates [Ca2+]i dynamics in metastatic PCa cell lines that mimic the progression of PCa to CRPC: (i) well differentiated LNCaP cells that require androgen for survival, and (ii) poorly differentiated, highly aggressive androgen-insensitive prostate cancer (AIPC) PC3 and DU145 cells. In AIPC cells, ATP induces a fast rise in [Ca2+]i, due to release from intracellular stores and sensitive to phospholipase C inhibitors, while LNCaP cells do not respond to ATP challenge. Moreover, AIPC cells showed a reduced capacity to store Ca2+ in thapsigargin-sensitive stores and limited store-operated calcium entry, with respect to androgen-dependent LNCaP cells. Finally, green tea extract causes [Ca2+]i elevation and inhibits proliferation in PC3 and DU145 cells, but is ineffective in LNCaP cells. The consequences of these differences are discussed and interpreted in this study with reference to previously proposed models for Ca2+ dependence of prostate carcinogenesis

Role of calcium channels in heavy metal toxicity

Cellular membranes are basically impermeable to ions and have developed specific pathways (channels, transporters or pumps) to facilitate metal translocation. These physiological carriers are not ideally selective and their specificity spectrum may include xenobiotic species, such as toxic metals whose availability in the environment has increased enormously in industrial times. I have studied the pathways of influx of two toxic metals, lead (Pb) and cadmium (Cd) in mammalian cells. Both metals interact with Ca-binding sites, but their ability to mimic Ca is different. Cd appears to permeate the cell membrane mainly through the same pathways as Ca, while Pb is also rapidly taken up in different cell types by passive transport systems that are distinct from Ca channels and independent of specific stimuli. To further elucidate the role of voltage-dependent Ca channels (VDCC) in Cd uptake, I compared the effect of this metal in two Chinese hamster ovary (CHO) cell lines, a wild type and modified cell line, which was permanently transfected with an L-type VDCC. Both cultures were subjected to brief (30-60 min) exposure to 50-100 ?M Cd in serum-free culture medium. Cell death was evident after 18-24 h with comparable features in both cell lines. Cell shrinkage, quantified by cell capacitance measurements, and metal accumulation, measured by atomic absorption spectroscopy, were also comparable in the two cell lines. However, in the permanently transfected cells, the effect of Cd treatment was partially prevented by nimodipine (VDCC antagonist) and enhanced by BayK8644 (VDCC agonist). I concluded that, although VDCC represent a pathway of Cd entry and participate in Cd-induced toxicity, as demonstrate by the effect of dihydropyridine (DHP) modifiers, expression of L-type Ca channels is not sufficient to modify Cd accumulation and sensitivity to a toxicological significant extent. Thus both Cd and Pb can take advantage of VDCC to permeate the membrane, but these transport proteins are not the only, and frequently not the most important, pathways of permeation

Observations on the Enamel of Odontomas

The morphological study of odontomas provides an alternative model for observing the formation of dental tissues, since different maturing stages are present simultaneously. Investigations were performed on decalcified samples (using light microscopy and transmission electron microscopy) and on undecalcified samples of complex odontoma enamel (using transmission electron microscopy). Simultaneous presence of prismatic enamel at various maturing stages with different structural characteristics was observed. Such enamel was sometimes associated with layers of ameloblastic cells with characteristics of cells in functional activity. In other sites, the enamel did not present a prismatic structure but it appeared as unstructured material clusters with abundant organic component. It was concluded that the theory according to which an ecto-mesenchymal inductive failure occurs in odontomas is not confirmed. The defect seen at the beginning of the differentiated and anomalous tissue maturation may be related to latest events in the development of the enamel organ. In this regard, it was concluded that such events involve the efficiency of the ameloblasts and the possible alterations in the organic matrix

An epistatic mini-circuitry between the transcription factors Snail and HNF4a controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

Preservation of the epithelial state involves the stable repression of EMT program while maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes, may provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4, directly represses the expression of the epithelial microRNAs-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4, previously identified as a transcriptional repressor of Snail, induces the microRNAs-34a and -200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4 and microRNAs -200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation

YAP integrates the regulatory Snail/HNF4α circuitry controlling epithelial/hepatocyte differentiation

Yes-associated protein (YAP) is a transcriptional co-factor involved in many cell processes, including development, proliferation, stemness, differentiation, and tumorigenesis. It has been described as a sensor of mechanical and biochemical stimuli that enables cells to integrate environmental signals. Although in the liver the correlation between extracellular matrix elasticity (greatly increased in the most of chronic hepatic diseases), differentiation/functional state of parenchymal cells and subcellular localization/activation of YAP has been previously reported, its role as regulator of the hepatocyte differentiation remains to be clarified. The aim of this study was to evaluate the role of YAP in the regulation of epithelial/hepatocyte differentiation and to clarify how a transducer of general stimuli can integrate tissue-specific molecular mechanisms determining specific cell outcomes. By means of YAP silencing and overexpression we demonstrated that YAP has a functional role in the repression of epithelial/hepatocyte differentiation by inversely modulating the expression of Snail (master regulator of the epithelial-to-mesenchymal transition and liver stemness) and HNF4α (master regulator of hepatocyte differentiation) at transcriptional level, through the direct occupancy of their promoters. Furthermore, we found that Snail, in turn, is able to positively control YAP expression influencing protein level and subcellular localization and that HNF4α stably represses YAP transcription in differentiated hepatocytes both in cell culture and in adult liver. Overall, our data indicate YAP as a new member of the HNF4/Snail epistatic molecular circuitry previously demonstrated to control liver cell state. In this model, the dynamic balance between three main transcriptional regulators, that are able to control reciprocally their expression/activity, is responsible for the induction/maintenance of different liver cell differentiation states and its modulation could be the aim of therapeutic protocols for several chronic liver diseases

China en África: la cooperación sanitaria en el marco de la pandemia

La declaración estado de pandemia mundial en marzo de 2020 por parte de la OMS, luego de que extendiera al mundo la epidemia de COVID-19 desatada en Wuhan, fue el marco en el cual se puso a prueba la capacidad cooperativa china para dar respuesta globalmente y una vez más África se constituyó en un terreno de evidencias. La intervención de China en la respuesta a la crisis ocasionada en África por el COVID- 19 fue rápida y atinada, podría decirse que arribaron casi en simultáneo. Apenas se hicieron públicos los primeros casos de COVID-19 en África Subsahariana, en el mes de febrero de 2020 (BBC, 2020) y en consonancia con los acuerdos firmados en la última Cumbre de la FOCAC (Foro para la Cooperación entre China y África) realizado en 2018, el gobierno chino se comprometió en ayudar a aquellos países con sistemas de salud débiles para fortalecer sus capacidades frente al coronavirus. Si bien la pandemia no ha finalizado y la actuación china en África dista de haber culminado en lo que a la lucha contra la pandemia se refiere, en el siguiente artículo nos proponemos exponer acciones y elementos discursivos que dan cuenta de la magnitud de la ayuda china y de la relevancia que la misma tiene para el futuro del continente.Departamento de ÁfricaInstituto de Relaciones Internacionale

Il fenomeno della “resilience”

The study of the effects of child mistreatment, including sexual abuse, neglect and physical abuse, suggest that the interaction between exposure to adverse experience and risk or protective factors produces a variety of phenotypic expressions; this variety includes both individuals with severe psychopathology and individuals seeming well-adapted. In substance, positive adaptation means competence with respect to behavioral, social and/or cognitive functioning (despite past or present maltreatment) and well-adapted individuals are considered resilient. This adjective is derived from resilience, term that has been improperly used as synonym of invulnerability, stress-resistance, adaptability. Reviews of literature show that resilience is currently considered a dynamic and multidimensional developmental process involving positive adaptation within the context of significant adversity. There are several variables that influence, in a positive or negative manner, the development of resilience: protective and risks factors. Investigators have identified a triad of protective factors: 1) dispositional / temperamental attributes of the child, including higher cognitive ability, positive self-esteem, internal "locus of control" for good events, external "locus of control" for abuse (or external attribution of blame), spirituality, ego-resiliency, coping strategies; 2) familial cohesion; 3) extrafamilial support. The three elements of this triad often collaborate in determining resilience, in opposition to risks factors usually coexisting in maltreatment situations (as low socio-economic level or maternal depression). In research on resilience some methodological features are more important in regard to data collection: all the sources of data, as parents', teachers' and peers' ratings, with the help of intelligence and achievement tests and grades in school, but also children’s self-reports.Lo studio delle conseguenze del maltrattamento infantile (abuso sessuale, violenza fisica e abbandono) ha suggerito che il risultato dell’interazione tra l’esposizione ad un’esperienza negativa ed i fattori protettivi e fattori di rischio presenti sia nella situazione che nel soggetto, sia costituito da una vasta gamma di espressioni fenotipiche ai cui estremi si trovano, da una parte, soggetti affetti da gravi psicopatologie e, dall’altra, individui che apparentemente mostrano un buon adattamento; un buon adattamento è costituito, in sostanza, da un funzionamento competente dal punto di vista comportamentale, sociale e cognitivo. Questi individui sono stati definiti “resilient”, che mal si traduce nella nostra lingua come “resiliente”, “elastico” o “capace di recupero o ripresa”. L’aggettivo “resilient” deriva a sua volta dal termine “resilience” (in italiano resilienza, elasticità, capacità di recupero o ripresa). Dall’esame della letteratura riguardante la “resilience” è emerso che, allo stato attuale, essa è definita come un processo dinamico di sviluppo, di natura multidimensionale, che implica un adattamento positivo all’interno di un contesto significativamente avverso. Lo sviluppo della “resilience” dipende in stretta misura dalla presenza di numerose variabili, di cui alcune si associano in modo positivo alla “resilience” (fattori protettivi) ed altre in modo negativo (fattori di rischio). Riguardo i fattori protettivi, i ricercatori ne hanno individuato una triade: 1) le caratteristiche psicologiche individuali, che comprendono le capacità cognitive spiccate, l’elevata autostima, il “locus of control” interno, per gli eventi positivi, e il “locus of control” esterno, per l’abuso (consistente nell’attribuzione esterna di colpa), la spiritualità, la “ego-resiliency” (elasticità o malleabilità), le strategie per affrontare il trauma (“coping strategies”) sia negative che soprattutto positive; 2) le relazioni familiari calde e sicure; 3) la presenza di un contesto extrafamiliare supportante ed affidabile. I tre elementi della triade, in realtà, cooperano nel determinismo della “resilience” contrastando, invece, l’effetto negativo dei fattori di rischio che spesso coesistono nelle situazioni di maltrattamento (come il basso livello socio-economico o la presenza di una madre affetta da depressione). Particolare rilievo assumono le modalità di raccolta dati: la maggior parte degli autori consiglia di utilizzare notizie provenienti dai genitori, dagli insegnanti e dai coetanei, ma anche dai soggetti in questione tramite autovalutazioni, test per valutare l’intelligenza e le capacità personali, risultati scolastici

China en África: la cooperación sanitaria en el marco de la pandemia

La cooperación china en África se remonta a los años cincuenta, cuando el régimen maoísta procuraba obtener reconocimiento y apoyo internacional. Durante las décadas siguientes la presencia china se mantuvo, con matices e intensidades variadas, para irrumpir finalmente con fuerza en el siglo XXI. África se convirtió entonces en el escenario de demostración de la capacidad china para promover el desarrollo en el Sur en base a los principios de solidaridad, no injerencia y equidad. La Cooperación Sur-Sur (CSS) china en el continente se caracterizó por desplegar programas vinculados a la generación de infraestructura y al fortalecimiento de capacidades productivas, pero también incluyó la cooperación sanitaria. En efecto, el concepto de la Ruta de la Seda Sanitaria se presentó en 2017 en el marco de la Iniciativa de la Franja y la Ruta como un nuevo pilar basado en un acuerdo con la Organización Mundial de la Salud (OMS). En dicha ocasión el Director General de la OMS destacó que la propuesta contenía lo fundamental para lograr la cobertura sanitaria universal: infraestructuras, acceso a medicamentos, recursos humanos y una plataforma para compartir experiencias y promover prácticas óptimas (Tedros, 2017).Fil: Marchetti, Agustina. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Morasso, Carla. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentin

SARS-CoV-2 and the nervous system: review on pathogenesis of nervous system SARS-CoV-2 damage

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Synthesis of kainoids via a highly stereoselective hydroformylation of kainic acid.

An efficient prepn. of a series of secondary amines, structurally related to the kainic acid scaffold, is described.  Naturally occurring (-)-α-kainic acid was hydroformylated with complete terminal selectivity and high stereoselectivity.  The stereochem. of the product was investigated through the ROESY and HETLOC spectra of the corresponding 2,4-dinitrophenylhydrazone, showing the presence of a single diastereoisomer with rotamers related to the presence of the Boc group.  The aldehyde was used as a platform to prep. amines by reductive amination in ionic liqs