The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Luis F Alguacil - One of the best experts on this subject based on the ideXlab platform.
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perinatal undernourishment provokes long lasting alterations of clusterin and Fumarate Hydratase expression in the rat nucleus accumbens
Nutritional Neuroscience, 2021Co-Authors: Carmen Rodriguezrivera, Carmen Gonzalezmartin, Elisa Fernandezmillan, Carmen Alvarez, Fernando Escriva, Luis F AlguacilAbstract:BACKGROUND Background: Perinatal malnutrition seems to provoke important neurochemical alterations in the brain that lead to higher vulnerability to develop neuropsychiatric disorders in the adulthood. OBJECTIVES We have examined the persistence and reversibility of the changes induced by perinatal undernourishment on the expression of Fumarate Hydratase in the rat nucleus accumbens, bearing in mind that this expression has been previously linked with addictive disorders. Clusterin, a multifunctional protein known to be neuroprotective and possibly related to addiction in humans, was studied in parallel. METHODS Female Wistar rats underwent a severe restriction of food during gestation and lactation. Upon weaning, a subgroup of undernourished animals was switched to normal chow and another one continued under food restriction. Control rats and their mothers were fed on chow along the experiment. Fumarate Hydratase and clusterin were quantified by western blot after five months of postnatal life in the three experimental groups. RESULTS Food restriction along the whole experimental period provoked a marked upregulation of both clusterin and Fumarate Hydratase in the mitochondrial fraction of the nucleus accumbens. In the case of clusterin, this upregulation was also observed in the cytosolic fraction of the nucleus accumbens. When undernourishment was limited to gestation and lactation the two proteins appeared downregulated with respect to controls. CONCLUSION The results are consistent with the idea that perinatal malnutrition provokes marked changes in brain neurochemistry that are not fully corrected by the rehabilitation of normal feeding and could be linked to behavioural disturbances in the adulthood, that is, increased vulnerability to addiction.
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Undernutrition upregulates Fumarate Hydratase in the rat nucleus accumbens.
Metabolic brain disease, 2012Co-Authors: Esther Lizárraga-mollinedo, Carmen Alvarez, Fernando Escriva, Elisa Fernández-millán, Carmen González-martín, Elisabet Salas, José Manuel Pérez-ortiz, Luis F AlguacilAbstract:Previous comparative studies of Fumarate Hydratase (FH) protein density revealed that the enzyme was overexpressed in the striatum of rodents that are less influenced by rewarding stimuli, from cocaine to food. Therefore, we recently proposed FH as a potential striatal biomarker of brain reward deficiency and addiction vulnerability. This work has been focused to investigate FH activity in the Nucleus Accumbens (NAc) of undernourished rats, taking into account that malnutrition has been related to increased responsiveness to food and drug reward. To this end, we have studied adult female Wistar rats severely food restricted from the 16th day of intrauterine life until adulthood. Animals were sacrificed to dissect the NAc and obtain mitochondrial and cytosolic fractions after homogenisation and centrifugation. FH activity was measured by conversion of malate to Fumarate, and protein levels were compared by Western blot analysis when fractions showed differences in activity. Undernutrition did not change cytosolic FH activity but led to a marked increase of mitochondrial FH activity (72 %) and protein content (50 %) in the NAc. This change was in the opposite direction that one would predict if it was related to addiction vulnerability of some kind, but strongly suggests that mitochondrial FH needs to be at some optimal level for normal reward responsiveness.
Christian Frezza - One of the best experts on this subject based on the ideXlab platform.
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Fumarate Hydratase in cancer: A multifaceted tumour suppressor.
Seminars in cell & developmental biology, 2019Co-Authors: Christina Schmidt, Marco Sciacovelli, Christian FrezzaAbstract:Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as Fumarate Hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of Fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that Fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the stepwise neoplastic progression after FH loss.
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Fumarate Hydratase loss promotes mitotic entry in the presence of dna damage after ionising radiation
Cell Death and Disease, 2018Co-Authors: Timothy Isaac Johnson, Ana S.h. Costa, Ashley N Ferguson, Christian FrezzaAbstract:An altered response to DNA damage is commonly associated with genomic instability, a hallmark of cancer. Fumarate Hydratase (FH) was recently characterised as a DNA repair factor required in non-homologous end-joining (NHEJ) through the local production of Fumarate. Inactivating germline mutations in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a cancer syndrome characterised by accumulation of Fumarate. Recent data indicate that, in FH-deficient cells, Fumarate suppresses homologous recombination DNA repair upon DNA double-strand breaks, compromising genome integrity. Here, we show that FH loss confers resistance to DNA damage caused by ionising radiation (IR), and promotes early mitotic entry after IR in a Fumarate-specific manner, even in the presence of unrepaired damage, by suppressing checkpoint maintenance. We also showed that higher levels of DNA damage foci are detectable in untreated FH-deficient cells. Overall, these data indicate that FH loss and Fumarate accumulation lead to a weakened G2 checkpoint that predisposes to endogenous DNA damage and confers resistance to IR.
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Post-translational regulation of metabolism in Fumarate Hydratase deficient cancer cells.
Metabolic engineering, 2017Co-Authors: Emanuel Gonçalves, Christian Frezza, Marco Sciacovelli, Ana S.h. Costa, Timothy Isaac Johnson, Daniel Machado, Maxine Gia Binh Tran, Julio Saez-rodriguezAbstract:Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in Fumarate Hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.
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Metabolic Alterations in Fumarate Hydratase Deficient Cells
Proceedings of The 2nd International Electronic Conference on Metabolomics, 2017Co-Authors: Christian FrezzaAbstract:Mutations of the tricarboxylic acid cycle (TCA cycle) enzyme Fumarate Hydratase (FH) cause the hereditary cancer syndrome Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). FH-deficient renal cancers are highly aggressive and metastasise even when small, leading to an abysmal clinical outcome. How these cells survive without FH and how they become transformed is still under investigation. Today, I will show our data on the metabolic reprogramming triggered by the loss of FH, which induces, amongst various changes, the Fumarate-mediated succination of the iron-sulfur-cluster proteins ISCU1, NFU1, and Bola1/3. Of note, this post translational modification leads to defects in iron-sulfur cluster biogenesis and complex I deficiency. These results could help to explain the profound alteration of mitochondrial metabolism in cells that lack FH.
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Post-translational regulation of metabolism in Fumarate Hydratase deficient cancer cells
2017Co-Authors: Emanuel Gonçalves, Christian Frezza, Marco Sciacovelli, Ana S.h. Costa, Timothy Isaac Johnson, Daniel Machado, Julio Saez-rodriguezAbstract:Deregulated signal transduction pathways and energy metabolism are hallmarks of cancer and both play a fundamental role in the process of tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in Fumarate Hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we show that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers.
Robert A Soslow - One of the best experts on this subject based on the ideXlab platform.
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Novel Fumarate Hydratase Mutation in Siblings With Early Onset Uterine Leiomyomas and Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome.
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists, 2018Co-Authors: V. Gunnala, Robert A Soslow, Nigel Pereira, Mohamad Irani, Debra Lilienthal, Edyta C. Pirog, Thomas A. Caputo, Rony T. Elias, Isaac Kligman, Zev RosenwaksAbstract:Hereditary leiomyomatosis renal cell cancer syndrome is an autosomal dominant disorder characterized by uterine and cutaneous leiomyomas and increased predisposition to renal cell carcinoma, papillary type II. The syndrome is caused by heterozygous mutations to the Fumarate Hydratase (FH) gene located on chromosome 1. Affected females generally present with early onset, atypical uterine leiomyomas and cutaneous findings, however, delays in diagnosis are very common in patients with isolated uterine findings. We present a case series of 2 sisters in their 20s who presented with isolated uterine leiomyomas and were found to carry a novel mutation for the Fumarate Hydratase gene. One patient was referred for treatment of infertility and recurrent miscarriages and the other was referred for acute symptomatic anemia due to myomas. Prompt diagnosis of hereditary leiomyomatosis renal cell cancer was made due to a high index of clinical suspicion based on early onset disease and familial clustering as well as characteristic pathologic findings on uterine leiomyoma surgical specimen. Timely diagnosis not only allowed for genetic counseling and renal cancer surveillance, but also for fertility counseling given the increased morbidity associated with uterine leiomyoma due to hereditary leiomyomatosis and renal cell cancer syndrome.
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Uterine smooth muscle tumors with features suggesting Fumarate Hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry
Modern Pathology, 2014Co-Authors: Carolina Reyes, Yevgeniy Karamurzin, Norma Frizzell, Karuna Garg, Daisuke Nonaka, Ying-bei Chen, Robert A SoslowAbstract:Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to a somatic Fumarate Hydratase mutation. Germline mutations account for the hereditary leiomyomatosis and renal cell carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered Fumarate Hydratase leads to Fumarate accumulation in affected cells with formation of S -(2-succino)-cysteine, which can be detected with the polyclonal antibody. High levels of these modified cysteine residues are found characteristically in Fumarate Hydratase-deficient cells but not in normal tissues or tumors unassociated with hereditary leiomyomatosis and renal cell carcinoma syndrome. We hypothesized that S -(2-succino)-cysteine-positive leiomyomas, indicating Fumarate Hydratase aberration, have morphologic features that differ from those without S -(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth-muscle tumors were prospectively analyzed for features suggesting hereditary leiomyomatosis and renal cell carcinoma syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding nine cases. Germline genetic testing for Fumarate Hydratase mutations was performed in three cases. A detailed morphological analysis was undertaken, and S -(2-succino)-cysteine immunohistochemical analysis was performed with controls from a tissue microarray (leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)). Of the nine study cases, four had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S -(2-succino)-cysteine antibody. Two of three tested patients had germline Fumarate Hydratase mutations. Only one leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth-muscle tumors with Fumarate Hydratase aberration demonstrate morphological reproducibility across cases and S -(2-succino)-cysteine immuno-positivity. Although the features described are not specific for the germline Fumarate Hydratase mutation or the hereditary leiomyomatosis and renal cell carcinoma syndrome, their presence should suggest Fumarate Hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible hereditary leiomyomatosis and renal cell carcinoma.
Fernando Escriva - One of the best experts on this subject based on the ideXlab platform.
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perinatal undernourishment provokes long lasting alterations of clusterin and Fumarate Hydratase expression in the rat nucleus accumbens
Nutritional Neuroscience, 2021Co-Authors: Carmen Rodriguezrivera, Carmen Gonzalezmartin, Elisa Fernandezmillan, Carmen Alvarez, Fernando Escriva, Luis F AlguacilAbstract:BACKGROUND Background: Perinatal malnutrition seems to provoke important neurochemical alterations in the brain that lead to higher vulnerability to develop neuropsychiatric disorders in the adulthood. OBJECTIVES We have examined the persistence and reversibility of the changes induced by perinatal undernourishment on the expression of Fumarate Hydratase in the rat nucleus accumbens, bearing in mind that this expression has been previously linked with addictive disorders. Clusterin, a multifunctional protein known to be neuroprotective and possibly related to addiction in humans, was studied in parallel. METHODS Female Wistar rats underwent a severe restriction of food during gestation and lactation. Upon weaning, a subgroup of undernourished animals was switched to normal chow and another one continued under food restriction. Control rats and their mothers were fed on chow along the experiment. Fumarate Hydratase and clusterin were quantified by western blot after five months of postnatal life in the three experimental groups. RESULTS Food restriction along the whole experimental period provoked a marked upregulation of both clusterin and Fumarate Hydratase in the mitochondrial fraction of the nucleus accumbens. In the case of clusterin, this upregulation was also observed in the cytosolic fraction of the nucleus accumbens. When undernourishment was limited to gestation and lactation the two proteins appeared downregulated with respect to controls. CONCLUSION The results are consistent with the idea that perinatal malnutrition provokes marked changes in brain neurochemistry that are not fully corrected by the rehabilitation of normal feeding and could be linked to behavioural disturbances in the adulthood, that is, increased vulnerability to addiction.
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Undernutrition upregulates Fumarate Hydratase in the rat nucleus accumbens.
Metabolic brain disease, 2012Co-Authors: Esther Lizárraga-mollinedo, Carmen Alvarez, Fernando Escriva, Elisa Fernández-millán, Carmen González-martín, Elisabet Salas, José Manuel Pérez-ortiz, Luis F AlguacilAbstract:Previous comparative studies of Fumarate Hydratase (FH) protein density revealed that the enzyme was overexpressed in the striatum of rodents that are less influenced by rewarding stimuli, from cocaine to food. Therefore, we recently proposed FH as a potential striatal biomarker of brain reward deficiency and addiction vulnerability. This work has been focused to investigate FH activity in the Nucleus Accumbens (NAc) of undernourished rats, taking into account that malnutrition has been related to increased responsiveness to food and drug reward. To this end, we have studied adult female Wistar rats severely food restricted from the 16th day of intrauterine life until adulthood. Animals were sacrificed to dissect the NAc and obtain mitochondrial and cytosolic fractions after homogenisation and centrifugation. FH activity was measured by conversion of malate to Fumarate, and protein levels were compared by Western blot analysis when fractions showed differences in activity. Undernutrition did not change cytosolic FH activity but led to a marked increase of mitochondrial FH activity (72 %) and protein content (50 %) in the NAc. This change was in the opposite direction that one would predict if it was related to addiction vulnerability of some kind, but strongly suggests that mitochondrial FH needs to be at some optimal level for normal reward responsiveness.
Carmen Alvarez - One of the best experts on this subject based on the ideXlab platform.
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perinatal undernourishment provokes long lasting alterations of clusterin and Fumarate Hydratase expression in the rat nucleus accumbens
Nutritional Neuroscience, 2021Co-Authors: Carmen Rodriguezrivera, Carmen Gonzalezmartin, Elisa Fernandezmillan, Carmen Alvarez, Fernando Escriva, Luis F AlguacilAbstract:BACKGROUND Background: Perinatal malnutrition seems to provoke important neurochemical alterations in the brain that lead to higher vulnerability to develop neuropsychiatric disorders in the adulthood. OBJECTIVES We have examined the persistence and reversibility of the changes induced by perinatal undernourishment on the expression of Fumarate Hydratase in the rat nucleus accumbens, bearing in mind that this expression has been previously linked with addictive disorders. Clusterin, a multifunctional protein known to be neuroprotective and possibly related to addiction in humans, was studied in parallel. METHODS Female Wistar rats underwent a severe restriction of food during gestation and lactation. Upon weaning, a subgroup of undernourished animals was switched to normal chow and another one continued under food restriction. Control rats and their mothers were fed on chow along the experiment. Fumarate Hydratase and clusterin were quantified by western blot after five months of postnatal life in the three experimental groups. RESULTS Food restriction along the whole experimental period provoked a marked upregulation of both clusterin and Fumarate Hydratase in the mitochondrial fraction of the nucleus accumbens. In the case of clusterin, this upregulation was also observed in the cytosolic fraction of the nucleus accumbens. When undernourishment was limited to gestation and lactation the two proteins appeared downregulated with respect to controls. CONCLUSION The results are consistent with the idea that perinatal malnutrition provokes marked changes in brain neurochemistry that are not fully corrected by the rehabilitation of normal feeding and could be linked to behavioural disturbances in the adulthood, that is, increased vulnerability to addiction.
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Undernutrition upregulates Fumarate Hydratase in the rat nucleus accumbens.
Metabolic brain disease, 2012Co-Authors: Esther Lizárraga-mollinedo, Carmen Alvarez, Fernando Escriva, Elisa Fernández-millán, Carmen González-martín, Elisabet Salas, José Manuel Pérez-ortiz, Luis F AlguacilAbstract:Previous comparative studies of Fumarate Hydratase (FH) protein density revealed that the enzyme was overexpressed in the striatum of rodents that are less influenced by rewarding stimuli, from cocaine to food. Therefore, we recently proposed FH as a potential striatal biomarker of brain reward deficiency and addiction vulnerability. This work has been focused to investigate FH activity in the Nucleus Accumbens (NAc) of undernourished rats, taking into account that malnutrition has been related to increased responsiveness to food and drug reward. To this end, we have studied adult female Wistar rats severely food restricted from the 16th day of intrauterine life until adulthood. Animals were sacrificed to dissect the NAc and obtain mitochondrial and cytosolic fractions after homogenisation and centrifugation. FH activity was measured by conversion of malate to Fumarate, and protein levels were compared by Western blot analysis when fractions showed differences in activity. Undernutrition did not change cytosolic FH activity but led to a marked increase of mitochondrial FH activity (72 %) and protein content (50 %) in the NAc. This change was in the opposite direction that one would predict if it was related to addiction vulnerability of some kind, but strongly suggests that mitochondrial FH needs to be at some optimal level for normal reward responsiveness.
