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- Acetyl-L-Carnitine Improves Cell BioenergeticsPublication . Cunha, Lídia; Bravo, Joana; Costa, Pedro; Fernandes, Sílvia; Oliveira, Marta; Castro, Rosa; Metello, Luís F.; Summavielle, TeresaIntroduction: Acetyl-L-Carnitine (ALC), a natural occurring compound in all mammalian species, plays a variety of vital functions in the body. The most important are related to mitochondria, namely the transport of fatty acids for energy production through β oxidation and the control of acyl-CoA/CoA ratio. Due to this close interaction with cell bioenergetics, it plays a role in many diseases, especially those related to the mitochondria. We propose to characterize the action of ALC in mitochondrial bioenergetics and functional integrity.
- 3D vs 2D Cell Cultures in the Evaluation of Radiobiological Effects of Exposition to Low Doses - Medical Imaging Levels - of Ionizing RadiationPublication . Costa, Pedro; Caires, Hugo; Lemos, Joana; Cunha, Lídia; Bravo, Joana; Bravo, Isabel; Silva, Regina; Summavielle, Teresa; Metello, Luís F.Pretending to develop advanced biological models to study biological effects of low doses of ionizing radiation and following the actual policies on Animal Sciences, based on 3 R’s Rule (to Reduce, Refine and Replace) – that limits as much as possible the application of animal models – scientific research using cellular models is constantly increasing. Nevertheless, the intrinsic limitations of actual cellular models quite often had been recognized on a significant number of papers pointing a significant number of non-concordances between results obtained using in vitro and in vivo studies. Actually, an increasing number of authors admit that three-dimensional cell culture (and spheroid cell culture in particular) could represent an interesting solution and a step further on use of cellular models. The work here to be presented reflects the first phase on the use of this methodology on the study, evaluation and quantification of cellular effects of low doses – starting on medical imaging level - of exposition to ionizing radiation.
- The Role of Mitochondria in Acetyl-L-Carnitine Neuroprotective ActionPublication . Cunha, Lídia; Bravo, Joana; Costa, Pedro; Gonçalves, Raquel; Rodrigues, Catarina; Rodrigues, Adriano; Metello, Luís F.; Summavielle, TeresaIt is widely known that a number of chronic neurodegenerative disorders are related with dysfunctional mitochondria. Although it has been proposed that Acetyl-L-Carnitine (ALC) confers neuroprotection through mitochondria viability improvement, little is known concerning the molecular mechanisms involved. We propose to characterize the action of ALC in mitochondria bioenergetics and functional integrity.
- ALC Neuroprotection through autophagy and ups acitivityPublication . Bravo, Joana; Cunha, Lídia; Fernandes, Sílvia; Binienda, Zbigniew; Summavielle, TeresaAcetyl–L-carnitine (ALC) has beneficial effects in neurodegenerative diseases and was shown to be protective against exposure to methamphetamine (METH) reducing mitochondrial dysfunction and oxidative stress. However, the mechanisms underlying ALC action are still unknown, limiting its putative therapeutic use.
- The impact of psychostimulants on central and peripheral neuro-immune regulation: a scoping review of cytokine profiles and their implications for addictionPublication . Bravo, Joana; Magalhães, Catarina; Andrade, Elva B.; Magalhães, Ana; Summavielle, TeresaIt is now well-accepted that psychostimulants act on glial cells causing neuroinflammation and adding to the neurotoxic effects of such substances. Neuroinflammation can be described as an inflammatory response, within the CNS, mediated through several cytokines, reactive oxygen species, chemokines and other inflammatory markers. These inflammatory players, in particular cytokines, play important roles. Several studies have demonstrated that psychostimulants impact on cytokine production and release, both centrally and at the peripheral level. Nevertheless, the available data is often contradictory. Because understanding how cytokines are modulated by psychoactive substances seems crucial to perspective successful therapeutic interventions, here, we conducted a scoping review of the available literature. We have focused on how different psychostimulants impact on the cytokine profile. Publications were grouped according to the substance addressed (methamphetamine, cocaine, methylphenidate, MDMA or other amphetamines), the type of exposure and period of evaluation (acute, short- or long-term exposure, withdrawal, and reinstatement). Studies were further divided in those addressing central cytokines, circulating (peripheral) levels, or both. Our analysis showed that the classical pro-inflammatory cytokines TNF-α, IL-6, and IL-1β were those more investigated. The majority of studies have reported increased levels of these cytokines in the central nervous system after acute or repeated drug. However, studies investigating cytokine levels during withdrawal or reinstatement have shown higher variability in their findings. Although we have identified fewer studies addressing circulating cytokines in humans, the available data suggest that the results may be more robust in animal models than in patients with problematic drug use. As a major conclusion, an extensive use of arrays for relevant cytokines should be considered to better determine which cytokines, upon the classical ones, may be involved in the progression from episodic use to the development of addiction. A concerted effort is still necessary to address the link between peripheral and central immune players, including from a longitudinal perspective. Until there, the identification of new biomarkers and therapeutic targets to envision personalized immune-based therapeutics will continue to be unlikely.
- Neuron–microglia contact-dependent mechanisms attenuate methamphetamine-induced microglia reactivity and enhance neuronal plasticityPublication . Bravo, Joana; Ribeiro, Inês; Terceiro, Ana Filipa; Andrade, Elva B.; Portugal, Camila Cabral; Lopes, Igor M.; Azevedo, Maria M.; Sousa, Mafalda; Lopes, Cátia D. F.; Lobo, Andrea C.; Canedo, Teresa; Relvas, João Bettencourt; Summavielle, TeresaExposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP3R2-Ca2+-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation.
- A mouse model reproducing the pathophysiology of neonatal group B streptococcal infectionPublication . Bonifácio Andrade, Elva; Magalhães, Ana; Puga, Ana; Costa, Madalena; Bravo, Joana; Portugal, Camila Cabral; Ribeiro, Adília; Correia-Neves, Margarida; Faustino, Augusto; Firon, Arnaud; Trieu-Cuot, Patrick; Summavielle, Teresa; Ferreira, PaulaGroup B streptococcal (GBS) meningitis remains a devastating disease. The absence of an animal model reproducing the natural infectious process has limited our understanding of the disease and, consequently, delayed the development of effective treatments. We describe here a mouse model in which bacteria are transmitted to the offspring from vaginally colonised pregnant females, the natural route of infection. We show that GBS strain BM110, belonging to the CC17 clonal complex, is more virulent in this vertical transmission model than the isogenic mutant BM110∆cylE, which is deprived of hemolysin/cytolysin. Pups exposed to the more virulent strain exhibit higher mortality rates and lung inflammation than those exposed to the attenuated strain. Moreover, pups that survive to BM110 infection present neurological developmental disability, revealed by impaired learning performance and memory in adulthood. The use of this new mouse model, that reproduces key steps of GBS infection in newborns, will promote a better understanding of the physiopathology of GBS-induced meningitis.
- Mitochondrial function and acetyl-L-carnitine neuroprotectionPublication . Cunha, Lídia; Bravo, Joana; Gonçalves, Raquel; Metello, Luís F.; Rodrigues, Adriano; Summavielle, TeresaMitochondrial dysfunction is involved in a number of chronic neurodegenerative disorders. Acetyl-L-carnitine (ALC) has been proposed to confer effective neuroprotection by increasing mitochondria viability, but little is known regarding the molecular mechanisms involved in its action
- Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetaminePublication . Canedo, Teresa; Portugal, Camila Cabral; Socodato, Renato; Almeida, Tiago Oliveira; Terceiro, Ana Filipa; Bravo, Joana; Silva, Ana Isabel; Magalhães, João Duarte; Guerra-Gomes, Sónia; Oliveira, João Filipe; Sousa, Nuno; Magalhães, Ana; Relvas, João Bettencourt; Summavielle, TeresaMethamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.
- Evaluation of 99mTc-Sestamibi as a potential tool to investigate PgP activity in inflammationPublication . Costa, Pedro; Cunha, Lídia; Bravo, Joana; Alves, Cecília J.; Summavielle, Teresa; Metello, Luís F.In the XXI Century’s Society the scientific investigation process has been rowing steadily, and the field of the pharmaceutical research is one of the most enthusiastic and relevant. Here, it is very important to correlate bserved functional alterations with possibly modified drug bio distribution patterns. Cancer, inflammation and infection are processes that induce many olecular intermediates like cytokines, chemokines and other chemical complexes that an alter the pharmacokinetics of many drugs. One cause of such changes is hought to be the modulator action of these complexes in the P-Glycoprotein activity, because they can act like inducers/inhibitors of MDR-1 expression. This protein results from the expression of MDR-1 gene, and acts as an ATP energy-dependent efflux pump, withtheir substrates including many drugs, like antiretrovirals, anticancers, anti-infectives, immunosuppressants, steroids or opioids. Because of the lack of methods to provide helpful information in he investigation of in vivo molecular changes in Pgp activity during fection/infl ammation processes, and its value in the explanation of the altered drug harmacokinetic, this paper want to evaluate the potential utility of 99m Tc-Sestamibi scintigraphy during this kind of health sciences investigation. Although the aim is indeed to create a technique to the in vivo study of Pgp activity, this preliminary Project only reaches the in vitro study phase, assumed as the first step in a n evaluation period for a new tool development. Materials and Methods: For that reason , we are performing in vitro studies of influx and efflux of 99m Tc - Sestamibi ( that is a substrate of Pgp) in hepatocytes cell line (HepG2). We are interested in clarify the cellular behavior of this radiopharmaceutical in Lipopolysaccharide(LPS) stimulated cells ( well known in vitro model of inflammation) to possibly approve this methodology. To validate the results, the Pgp expression will be finally evaluated using Western Blot technique. Results: Up to this moment , we still don’t have the final results, but we have already enough data to let us believe that LPS stimulation induce a downregulation of MDR - 1, and consequently Pgp, which could conduce to a prolonged retention of 99m Tc - Sestamibi in the inflamed cells . Conclusions: If and when this methodology demonstrate the promising results we expect, one will be able to con clude that Nuclear Medicine is an important tool to help evidence based research also on this specific field .