Fisioloxía

Permanent URI for this collectionhttps://hdl.handle.net/10347/34419

Browse

Now showing 1 - 20 of 228

The cholinergic antagonist gymnodimine improves Aβ and tau neuropathology in an in vitro model of Alzheimer disease
(Karger, 2011-06-17) Alonso, Eva; Vale González, María del Carmen; Rodríguez Vieytes, Mercedes; Laferla, Frank M.; Giménez-Llort, Lydia; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Gymnodimine (GYM) is a marine phycotoxin with a macrocyclic imine structure, isolated from extracts of the dinoflagellate Karenia selliformis known to act as a cholinergic antagonist with subtype selectivity. However, no data on the chronic effects of this compound has been reported so far. In this work, we evaluated the effect of long term exposure of cortical neurons to gymnodimine in the progress of Alzheimer disease (AD) pathology in vitro. Treatment of cortical neurons with 50 nM gymnodimine decreased the intracellular amyloid beta (Aβ) accumulation and the levels of the hyperphosphorylated isoforms of tau protein recognized by AT8 and AT100 antibodies. These results are suggested to be mediated by the increase in the inactive isoform of the glycogen synthase kinase-3 (phospho GSK-3 Ser9), the decrease in the levels of the active isoform of the ERK1/2 kinase and the increase in acetylcholine (Ach) synthesis elicited by long term exposure of cortical neurons to the toxin. Moreover, gymnodimine decreased glutamate-induced neurotoxicity in vitro. Altogether these results indicate that the marine phycotoxin gymnodimine may constitute a valuable tool for the development of drugs to treat neurodegenerative diseases.
Synthetic ciguatoxin CTX 3C induces a rapid imbalance of neuronal excitability
(American Chemical Society, 2015-05-06) Martín, Víctor; Vale González, María del Carmen; Hirama, Masahiro; Yamashita, Shuji; Rubiolo Gaytán, Juan Andrés; Rodríguez Vieytes, Mercedes; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Ciguatera is a human global disease caused by the consumption of contaminated fish that have accumulated ciguatoxins (CTXs), sodium channel activator toxins. Symptoms of ciguatera include neurological alterations such as paraesthesiae, dysaesthesiae, depression, and heightened nociperception, among others. An important issue to understand these long-term neurological alterations is to establish the role that changes in activity produced by CTX 3C represent to neurons. Here, the effects of synthetic ciguatoxin CTX 3C on membrane potential, spontaneous spiking, and properties of synaptic transmission in cultured cortical neurons of 11–18 days in vitro (DIV) were evaluated using electrophysiological approaches. CTX 3C induced a large depolarization that decreased neuronal firing and caused a rapid inward tonic current that was primarily GABAergic. Moreover, the toxin enhanced the amplitude of miniature postsynaptic inhibitory currents (mIPSCs), whereas it decreased the amplitude of miniature postsynaptic excitatory currents (mEPSCs). The frequency of mIPSCs increased, whereas the frequency of mEPSCs remained unaltered. We describe, for the first time, that a rapid membrane depolarization caused by CTX 3C in cortical neurons activates mechanisms that tend to suppress electrical activity by shifting the balance between excitatory and inhibitory synaptic transmission toward inhibition. Indeed, these results suggest that the acute effects of CTX on synaptic transmission could underlie some of the neurological symptoms caused by ciguatera in humans.
Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons
(American Chemical Society, 2015-05-06) Martín, Víctor; Vale González, María del Carmen; Rubiolo Gaytán, Juan Andrés; Roel, María; Hirama, Masahiro; Yamashita, Shuji; Rodríguez Vieytes, Mercedes; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10–13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin. These findings identify an unanticipated role for ciguatoxin in the regulation of homeostatic plasticity in central neurons involving NaV channels and raise the possibility that some of the neurological symptoms of ciguatera might be explained by these compensatory mechanisms.
Design and synthesis of skeletal analogues of gambierol: Attenuation of amyloid-β and tau pathology with voltagegated potassium channel and N-methyl-D-aspartate receptor implications.
(American Chemical Society, 2012-04-04) Alonso, Eva; Fuwa, Haruhiko; Vale González, María del Carmen; Suga, Yuto; Goto, Tomomi; Konno, Yu; Sasaki, Makoto; Laferla, Frank M.; Rodríguez Vieytes, Mercedes; Giménez-Llort, Lydia; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (Kv channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure–activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage-gated potassium channels (Kv) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer’s disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (Aβ) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K+ currents, a reduction in the extra- and intracellular levels of Aβ, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-d-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of Kv channels as well as the molecular mechanism of Aβ metabolism modulated by NMDA receptors.
Effect of Gambierol and Its Tetracyclic and Heptacyclic Analogues in Cultured Cerebellar Neurons: A Structure−Activity Relationships Study
(American Chemical Society, 2012-08-15) Pérez, Sheila; Vale González, María del Carmen; Alonso, Eva; Fuwa, Haruhiko; Sasaki, Makoto; Konno, Yu; Goto, Tomomi; Suga, Yuto; Rodríguez Vieytes, Mercedes; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía; Universidade de Santiago de Compostela. Departamento de Fisioloxía
The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28═C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J.10, 4894−4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a “loss of function” effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 μg/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a “loss of function” effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases.
Differential Effects of Crambescins and Crambescidin 816 in Voltage-Gated Sodium, Potassium and Calcium Channels in Neurons
(American Chemical Society, 2012-12-27) Martín, Víctor; Vale González, María del Carmen; Bondu, Stéphanie; Thomas, Olivier P.; Rodríguez Vieytes, Mercedes; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Crambescins and crambescidins are two families of guanidine alkaloids from the marine sponge Crambe crambe. Although very little information about their biological effect has been reported, it is known that crambescidin 816 (Cramb816) blocks calcium channels in a neuroblastoma X glioma cell line. Taking this into account, and the fact that ion channels are frequent targets for natural toxins, we examined the effect of Cramb816 and three compounds from the crambescin family, norcrambescin A2 (NcrambA2), crambescin A2 (CrambA2), and crambescin C1 (CrambC1), in the main voltage-dependent ion channels in neurons: sodium, potassium, and calcium channels. Electrophysiological recordings of voltage gated sodium, potassium, and calcium currents, in the presence of these guanidine alkaloids, were performed in cortical neurons from embryonic mice. Different effects were discovered: crambescins inhibited K(+) currents with the following potency: NcrambA2 > CrambC1 > CrambA2, while Cramb816 lacked an effect. Only CrambC1 and Cramb816 partially blocked Na(+) total current. However, Cramb816 partially blocked Ca(2+) , while NcrambA2 did not. Since the blocking effect of Cramb816 on calcium currents has not been previously reported in detail, we further pharmacologically isolated the two main fractions of HVA Ca(2+) channels in neurons and investigated the Cramb816 effect on them. Here, we revealed that Cav1 or L-type calcium channels are the main target for Cramb816. These two families of guanidine alkaloids clearly showed a structure-activity relationship with the crambescins acting on voltage-gated potassium channels, while Cramb816 blocks the voltage-gated calcium channel Cav1 with higher potency than nifedipine. The novel evidence that Cramb816 partially blocked CaV and NaV channels in neurons suggests that this compound might be involved in decreasing the neurotransmitter release and synaptic transmission in the central nervous system. The findings presented here provide the first detailed approach on the different effects of crambescin and crambescidin compounds in voltage-gated sodium, potassium, and calcium channels in neurons and thus provide a basis for future studies.
Differential effects of ciguatoxin and maitotoxin in primary cultures of cortical neurons
(American Chemical Society, 2014-07-07) Martín, Víctor; Vale González, María del Carmen; Antelo, Álvaro; Hirama, Masahiro; Yamashita, Shuji; Rodríguez Vieytes, Mercedes; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Ciguatoxins (CTXs) and maitotoxins (MTXs) are polyether ladder shaped toxins derived from the dinoflagellate Gambierdiscus toxicus. Despite the fact that MTXs are 3 times larger than CTXs, part of the structure of MTXs resembles that of CTXs. To date, the synthetic ciguatoxin, CTX 3C has been reported to activate voltage-gated sodium channels, whereas the main effect of MTX is inducing calcium influx into the cell leading to cell death. However, there is a lack of information regarding the effects of these toxins in a common cellular model. Here, in order to have an overview of the main effects of these toxins in mice cortical neurons, we examined the effects of MTX and the synthetic ciguatoxin CTX 3C on the main voltage dependent ion channels in neurons, sodium, potassium, and calcium channels as well as on membrane potential, cytosolic calcium concentration ([Ca(2+)]c), intracellular pH (pHi), and neuronal viability. Regarding voltage-gated ion channels, neither CTX 3C nor MTX affected voltage-gated calcium or potassium channels, but while CTX 3C had a large effect on voltage-gated sodium channels (VGSC) by shifting the activation and inactivation curves to more hyperpolarized potentials and decreasing peak sodium channel amplitude, MTX, at 5 nM, had no effect on VGSC activation and inactivation but decreased peak sodium current amplitude. Other major differences between both toxins were the massive calcium influx and intracellular acidification produced by MTX but not by CTX 3C. Indeed, the novel finding that MTX produces acidosis supports a pathway recently described in which MTX produces calcium influx via the sodium-hydrogen exchanger (NHX). For the first time, we found that VGSC blockers partially blocked the MTX-induced calcium influx, intracellular acidification, and protected against the short-term MTX-induced cytotoxicity. The results presented here provide the first report that shows the comparative effects of two prototypical ciguatera toxins, CTX 3C and MTX, in a neuronal model. We hypothesize that the analogies and differences in the bioactivity of these two toxins, produced by the same microorganism, may be strongly linked to their chemical structure.
Determination of toxicity equivalent factors for paralytic shellfish toxins by electrophysiological measurements in cultured neurons
(American Chemical Society, 2011-07-18) Pérez, Sheila; Vale González, María del Carmen; Botana López, Ana María; Alonso, Eva; Rodríguez Vieytes, Mercedes; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Química Analítica, Nutrición e Bromatoloxía; Universidade de Santiago de Compostela. Departamento de Fisioloxía
The establishment of toxicity equivalent factors to develop alternative methods to animal bioassays for marine-toxin detection is an urgent need in the field of phycotoxin research. Paralytic shellfish poisoning (PSP) is one of the most severe forms of food poisoning. The toxins responsible for this type of poisoning are highly toxic natural compounds produced by dinoflagellates, which bind to voltage-gated Na+ channels causing the blockade of action potential propagation. In spite of the fact that several standards of PSP toxins are currently commercially available, there is scarcity of data on the biological activity of these toxins, a fact that limits the calculation of their toxicity equivalent factors. We have evaluated the potency of the commercial PSP toxin standards for their ability to inhibit voltage-dependent sodium currents in cultured neuronal cells by electrophysiological measurements. The in vitro potencies of the PSP toxin standards as indicated by their IC50 values were in the order Neosaxitoxin (NeoSTX) > decarbamoylsaxitoxin (dcSTX) > saxitoxin (STX) > gonyautoxin 1,4 (GTX1,4) > decarbamoylneosaxitoxin (dcNeoSTX) > gonyautoxin 2,3 (GTX2,3) > decarbamoylgonyautoxin 2,3 (dcGTX2,3) > gonyautoxin 5 (GTX5) > N-sulfocarbamoyl-gonyautoxin-2 and -3 (C1,2). The data obtained in this in vitro analysis correlated well with their previously reported toxicity values.
Hypothalamus-liver talks: whispers in the language of metabolism
(Springer, 2026-03-19) Ferreira, Vitor; Fernández González, Iara; Vattathara, Jane Jose; Rodríguez Díaz, Amanda; Fernández Sanmartín, Paola; Diéguez González, Carlos; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
Closely associated with the exponential increase of obesity and sedentary life, liver-related disorders are a major global health concern. Recent data suggest that the global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) among adults is of 32% and 5.1% for alcohol-related liver disease, with hepatic disorders contributing to 4% of global mortality, accounting for approximately 2 million deaths annually. Over the past two decades, the hypothalamus has emerged as a central hub in regulating whole body metabolic and energy homeostasis. Nevertheless, the interactome between the hypothalamus and the liver in the progression of liver metabolic dysfunctions, as well as its potential as a therapeutic target, remains poorly understood. In this review, we provide a comprehensive overview of the current knowledge regarding the hypothalamus-liver crosstalk, with a particular emphasis on the mechanisms underlying it. We explore how signals transmitted by different hormones can modulate these interactions, shedding light on their functional implications for hepatic regulation and systemic homeostasis through central signals.
Phyconeurotoxins
(Elsevier, 2025-08-29) Botana López, Luis Miguel; Raposo García, Sandra; Camiña García, María Mercedes; Vale González, María del Carmen; Botana López, Ana María; Louzao Ojeda, María del Carmen; Rodríguez Vieytes, Mercedes; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Fisioloxía; Universidade de Santiago de Compostela. Departamento de Química Analítica, Nutrición e Bromatoloxía; England, John D.
Phyconeurotoxins are marine compounds produced by 200 species of microalgae that target receptors in the nervous system. Some of the toxin groups are well recognized as potent neurotoxins, namely Brevetoxins, Cyclic Imines, Ciguatoxins, Domoic Acid, Saxitoxins, and Tetrodotoxins. Ciguatoxins are produced by microalgae but only reported in fish, and for this reason their toxicology and food safety poses a special difficulty. Tetrodotoxins are present in both fish and shellfish; they are produced by bacteria, but some microalgae have associated bacteria that produce the toxin. All other toxin groups are associated with shellfish toxicity. Okadaic acid analogs and Azaspiracids might be included in this group of neurotoxins, although their mode of toxicity is under scientific scrutiny, and in consequence they are not fully accepted neurotoxins. In general, phyconeurotoxins are very diverse in chemical structure and mechanism of action. They are privileged structures that interact with their receptors at very low concentrations. Only Saxitoxins and Domoic acid are clearly considered lethal toxins in mammals. It remains to be clarified the biological role of phycotoxins, as they are harmless to fish or feed-filtering molluscs.
Neural stem cells and glioblastoma stem cells: Redefining concepts
(Elsevier, 2026-02-04) Arce Vázquez, Víctor Manuel; González Rendo, Lara; Porres Ventín, Laura; González Álvarez, Valentina; Caamaño Teixeira, Sabela; Almengló Buzón, Cristina; Señarís Rodríguez, Rosa María; Costoya Puente, José Antonio; Universidade de Santiago de Compostela. Departamento de Medicina; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Fisioloxía
Stem cells (SCs) represent a distinctive population of undifferentiated cells with the extraordinary ability to self-renew and differentiate into multiple cell types. Owing to this, SCs play a crucial role in maintaining tissue homeostasis, providing a source for the replacement of cell losses due to normal wear and tear. In addition, SCs display an unquestioned therapeutic potential, which has resulted in the development of several cell therapies for the treatment of different types of diseases. However, despite their remarkable potential, the therapeutic use of SCs must still face several challenges, which include ethical, legal and technical issues. Ethical and legal concerns are mainly related to the use of SCs obtained from human embryos, while technical problems mostly arise from the difficulty of appropriately directing the differentiation of the SCs to meet the tissue´s needs and the occurrence of events such as immune rejections. In addition, the safety of SC-based therapies is also under debate. Although they may offer a useful and harmless treatment for many pathologies, including some incurable and/or life-threatening diseases, a potential risk of tumorigenicity may also exist in some cases. Accumulating evidence also implicates SCs as the origin of, at least, some types of cancer. This is the case of glioblastoma (GBM), the most prevalent glioma type in adults, whose origin has been related to postnatal neural stem cells (NSCs), mainly located in the subventricular zone (SVZ) and the dentate gyrus in the hippocampus. It has been proposed that these NSCs may give rise to glioblastoma stem cells (GSCs), which through complex interactions with the tumor microenvironment exert a crucial effect on tumor growth and development.
Hypothalamic wars: the last nanodelivery
(Springer, 2026-03-04) Fazal, Sajid; Vattathara, Jane Jose; López Pérez, Miguel A.; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
The hypothalamus plays important roles in maintaining overall body homeostasis and energy balance. Disruption of its normal functioning has been associated with the onset of various metabolic disorders in the body that arise from several genetic, immunological, and environmental factors or their combination. To combat this, developing treatment strategies that modulate the activity of the hypothalamus could be advantageous. Here, understanding the hypothalamus’s complex structure and function within the context of regulation of energy balance is important to identify treatment targets and to explore opportunities to modulate key metabolic pathways. Moreover, the unique sensitive position of the hypothalamus in the brain necessitates that treatment strategies that are developed are highly effective and specific, and do not cause any untoward effects at neighboring regions of the brain. This is further complicated by its protection through the blood-brain barrier (BBB) that highly regulates the entry of materials from the periphery, allowing entry of molecules only under specific conditions. In this regard, advanced multifunctional nanoparticulate drug-delivery systems can be of benefit as they have been explored for brain specific delivery. For this, nanoparticle chemistry, specific ligand expression, BBB penetration capability, biocompatibility, and immunogenicity among other physicochemical properties are important parameters that govern brain specific delivery. In this review, the role of hypothalamus in regulating energy metabolism, its structure and function and the effect of dysfunction on the onset of metabolic disorders are summarized. Furthermore, the use of nanoparticles for brain targeting and hypothalamic regulation, such as small extracellular vesicles targeting AMP-activated protein kinase (AMPK), along with the future of nanoparticle-based modulation of the hypothalamus is also discussed.
LEAP2 acts in hepatocytes and at central level, alleviates steatosis and inflammation but resistance in obese and aging
(Elsevier, 2026-01-20) Varela Miguéns, Marta; Quintela Vilariño, Carmen; Casado Masa, Sabela; Oliveira Diz, Tadeu de; Müller, Timo D.; Nogueiras Pozo, Rubén; Diéguez González, Carlos; Tovar Carro, Sulay A.; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Fisioloxía
Scope. Global increase in obesity and metabolic syndrome has led to a marked rise in comorbidities, with liver disease emerging as a major concern. Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over 30% of the population, making it the most prevalent liver disorder worldwide. Hepatic steatosis, hallmark of MAFLD, can progress to inflammation, fibrosis, steatohepatitis, and cirrhosis. Despite advances in elucidating its mechanisms, no effective pharmacological therapy exists to reverse disease progression. Ghrelin signaling axis has been implicated in energy and lipid homeostasis, and the recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous ghrelin receptor antagonist and inverse agonist has generated interest in its potential role in liver metabolism. The primary objective of this study was to evaluate LEAP2 on hepatocyte lipid metabolism and determine its capacity to prevent diet- and age-induced steatosis in vivo. Methods and results. We investigated LEAP2 actions on hepatocyte lipid metabolism using human and mouse hepatocyte cultures, also we did in vivo studies in mice with chronic central LEAP2 administration in models of diet-induced and age-related steatosis. LEAP2 inhibited lipid accumulation in hepatocytes and reduced hepatic lipid deposition in mice fed a standard diet. However, LEAP2 did not prevent high-fat diet–induced steatosis in young mice although it attenuated hepatic inflammation. In aged animals, LEAP2 failed to suppress age-associated inflammation and steatosis. Conclusion. LEAP2 has been identified as a novel regulator of hepatic lipid metabolism with the potential to counteract inflammation-associated steatosis, although its effects on age-related steatosis appear limited. Targeting the LEAP2–ghrelin axis may represent a promising therapeutic strategy; however, further studies are required to determine its efficacy in diet-induced hepatic disease.
Okadaic acid triggers NFκB and STAT3 phosphorylation followed by a release of inflammatory markers in human and mouse endothelial cells
(Springer, 2026-02-17) Nyback, Klara; Alfonso Rancaño, María Amparo; Alvariño Romero, Rebeca; Suzuki, Toshiyuki; Watanabe, Ryuichi; Uchida, Hajime; Rodríguez Vieytes, Mercedes; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Okadaic acid (OA) is a lipophilic phycotoxin that causes acute diarrhoea when ingested. OA is an inhibitor of protein phosphatase 2 A, but the mechanism of toxicity behind the diarrhoea remains unclear. OA modulated inflammatory markers in epithelial cells, however, the effect on endothelial cells, with a key role in the inflammatory cascade, has not been previously addressed. Therefore, the aim of the present work was to test the effect of OA in human (HMEC-1) and mouse (MS1) endothelial cells. After 3, 6 and 24 h of incubation in the presence of OA (10-1000 nM) cell viability was significantly reduced, showing a higher effect on human cells with half inhibitory concentrations (IC50) in HMEC-1 cells five times lower than in mouse cells. Furthermore, when cells were treated with OA, significant amounts of the proinflammatory mediators ROS, CD147, IL-6 and monocyte chemoattractant protein 1 (MCP-1) were detected. Some of these effects were observed only in HMEC-1 cells and around three hours earlier, pointing again to a higher sensitivity in human models. Finally, OA triggered phosphorylation of NFκB at 100 nM after 3 and 6 h of treatment, while the signal transducer and activator of transcription 3 (STAT3) was increased after 3 h but decreased after 6 h in both cell lines. Altogether, these data suggest that the toxic effect of OA in endothelial cells could be related with the activation of the inflammatory cascade.
Neuroprotective effects of furanoditerpenes from Spongia (Spongia) tubulifera through cyclophilin D modulation against ischemia/reperfusion injury in BV2 microglial cells
(American Chemical Society, 2026-03-11) Castedo Caldeiro, Noelia; Alfonso Rancaño, María Amparo; Alvariño Romero, Rebeca; Pech-Puch, Dawrin; Ageitos Castiñeiras, Lucía; Rodríguez González, Jaime; Rodríguez Vieytes, Mercedes; Jiménez González, Carlos; Botana López, Luis Miguel; Universidade de Santiago de Compostela. Departamento de Farmacoloxía; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Ischemia induces oxidative stress and mitochondrial dysfunction in microglia, contributing to neuro-inflammation and neuronal damage. Five furanoditerpenes 1–5, isolated from the marine sponge Spongia (Spongia) tubulifera, have previously shown neuroprotective effects related to their capacity to bind cyclophilin D (CypD), a protein involved in ischemia. In this study, the ability of compounds 1–5 to alleviate ischemic damage was evaluated on BV2 microglial cells. First, cells were incubated under oxygen deprivation for 6 h, and the five compounds were able to improve cell viability at micromolar concentrations (0.001–1 μM). Then, hypoxia was combined with the inflammatory stimulus lipopolysaccharide and with glucose deprivation, and Spongia tubulifera metabolites maintained their protective effects. When oxygen and glucose deprivation was followed by 6 h of reperfusion, compounds 1–5 also mitigated the damage produced on microglia. Moreover, these furanoditerpenes reduced reactive oxygen species overproduction and restored mitochondrial membrane potential, key factors in ischemic damage. This effect was mediated by the regulation of CypD since compounds 2, 4, and 5 reduced its expression under ischemia conditions. Finally, trans-well coculture experiments were performed between microglial and SH-SY5Y neuronal cells. In this assay, compounds 2, 4, and 5 protected neuronal cells from microglial-induced neurotoxicity under ischemia/reperfusion conditions. These findings suggest that S. tubulifera metabolites display mitochondrial-mediated antioxidant and cytoprotective effects under ischemic conditions through CypD modulation. Given the limitations of current Cyps inhibitors like cyclosporin A, compounds 1–5 are promising therapeutic candidates for ischemia-related diseases, such as stroke
Understanding the Factors That Influence the Antioxidant Activity of Manganosalen Complexes with Neuroprotective Effects
(MDPI, 2024-02-22) Rouco Méndez, Lara; Alvariño Romero, Rebeca; Alfonso Rancaño, María Amparo; Fernández-Fariña, Sandra; González Noya, Ana María; Martínez Calvo, Miguel; Pedrido Castiñeiras, Rosa; Rodríguez Silva, Laura; Maneiro Maneiro, Marcelino; Universidade de Santiago de Compostela. Departamento de Química Inorgánica; Universidade de Santiago de Compostela. Departamento de Fisioloxía; Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica
Manganosalen complexes are a class of catalytic antioxidants with beneficial effects against different neurological disorders according to various in vitro and in vivo studies. The interest in the factors that determine their antioxidant activity is based on the fact that they are key to achieving more efficient models. In this work, we report a set of new manganosalen complexes, thoroughly characterized in the solid state and in solution by different techniques. The chelating Schiff base ligands used were prepared from condensation of different substituted hydroxybenzaldehydes with 1,2-diaminoethane and 1,3-diaminopropane. The antioxidant activity of the new models was tested through superoxide dismutase and catalase probes in conjunction with the studies about their neuroprotective effects in human SH-SY5Y neuroblastoma cells in an oxidative stress model. The ability to scavenge excess reactive oxygen species (ROS) varied depending on the manganosalen models, which also yielded different improvements in cell survival. An assessment of the different factors that affect the oxidant activity for these complexes, and others previously reported, revealed the major influence of the structural factors versus the redox properties of the manganosalen complexes.
Scalable Copper Sulfide Formulations for Super-Resolution Optoacoustic Brain Imaging in the Second Near-Infrared Window
(Wiley, 2024) Tang, Lin; Vidal Figueroa, Anxo; Torres Caldas, Ana María; Razansky, Daniel; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Optoacoustic imaging offers label-free multi-parametric characterization of cerebrovascular morphology and hemodynamics at depths and spatiotemporal resolution unattainable with optical microscopy. Effective imaging depth can greatly be enhanced by employing photons in the second near-infrared (NIR-II) window. However, diminished absorption by hemoglobin along with a lack of suitable contrast agents hinder an efficient application of the technique in this spectral range. Herein, copper sulfide (CuS) micro- and nano-formulations for multi-scale optoacoustic imaging in the NIR-II window are introduced. Dynamic contrast enhancement induced by intravenously administered CuS nanoparticles facilitated visualization of blood perfusion in murine cerebrovascular networks. The individual calcium carbonate microparticles carrying CuS are further shown to generate sufficient responses to enable super-resolution microvascular imaging and blood flow velocity mapping with localization optoacoustic tomography.
Food preference wars: the glucoprivation menace
(Elsevier, 2025-12-11) Ferreira, Vitor; López Pérez, Miguel A.; Universidade de Santiago de Compostela. Departamento de Fisioloxía; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
Exosomal ncRNAs in reproductive cancers
(Oxford University Press, 2025) Kowalczyk, Alicja; Wrzecińska, Marcjanna; Gałȩska, Elzbieta; Czerniawska-Piątkowska, Ewa; Camiña García, María Mercedes; Araujo, Jose P.; Dobrzański, Zbigniew; Universidade de Santiago de Compostela. Departamento de Fisioloxía
Extracellular vesicles, particularly exosomes, play a pivotal role in the cellular mechanisms underlying cancer. This review explores the various functions of exosomes in the progression, growth, and metastasis of cancers affecting the male and female reproductive systems. Exosomes are identified as key mediators in intercellular communication, capable of transferring bioactive molecules such as microRNAs, proteins, and other nucleic acids that influence cancer cell behavior and tumor microenvironment interactions. It has been shown that non-coding RNAs transported by exosomes play an important role in tumor growth processes. Significant molecules that may serve as biomarkers in the development and progression of male reproductive cancers include miR-125a-5p, miR-21, miR-375, the miR-371 ∼ 373 cluster, and miR-145-5p. For female reproductive cancers, significant microRNAs include miR-26a-5p, miR-148b, miR-205, and miRNA-423-3p. This review highlights the potential of these noncoding RNAs as biomarkers and prognostics in tumor diagnostics. Understanding the diverse roles of exosomes may hold promise for developing new therapeutic strategies and improving treatment outcomes for cancer patients.
Tex10 coordinates epigenetic control of super-enhancer activity in pluripotency and reprogramming
(Cell Press, 2015-06-04) Ding, Junjun; Huang, Xin; Shao, Ningyi; Zhou, Hongwei; Lee, Dung-Fan; Faiola, Francesco; Fidalgo Pérez, Miguel Ángel; Guallar Artal, Diana; Saunders, Arven; Shliaha, Pavel V.; Wang, Hailong; Waghray, Avinash; Papatsenko, Dmitri; Sánchez Priego, Carlos; Li, Dan; Yuan, Ye; Lemischka, Ihor R.; Shen, Li; Kelley, Kevin; Deng, Haiteng; Shen, Xiaohua; Wang, Jianlong; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Fisioloxía
Super-enhancers (SEs) are large clusters of transcriptional enhancers that are co-occupied by multiple lineage-specific transcription factors driving expression of genes that define cell identity. In embryonic stem cells (ESCs), SEs are highly enriched for the core pluripotency factors Oct4, Sox2, and Nanog. In this study, we sought to dissect the molecular control mechanism of SE activity in pluripotency and reprogramming. Starting from a protein interaction network surrounding Sox2, we identified Tex10 as a key pluripotency factor that plays a functionally significant role in ESC self-renewal, early embryo development, and reprogramming. Tex10 is enriched at SEs in a Sox2-dependent manner and coordinates histone acetylation and DNA demethylation at SEs. Tex10 activity is also important for pluripotency and reprogramming in human cells. Our study therefore highlights Tex10 as a core component of the pluripotency network and sheds light on its role in epigenetic control of SE activity for cell fate determination

Browse

Recent Submissions