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  1. Article ; Online: Role of misfolding in rare enzymatic deficits and use of pharmacological chaperones as therapeutic approach

    Gioena Pampalone / Silvia Grottelli / Leonardo Gatticchi / Emilia Maria Lombardi / Ilaria Bellezza / Barbara Cellini

    Frontiers in Bioscience-Landmark, Vol 26, Iss 12, Pp 1627-

    2021  Volume 1642

    Abstract: Cells have evolved sophisticated molecular control systems to maximize the efficiency of the folding process. However, any subtle alteration of the environment or the protein can lead to misfolding or affect the conformational plasticity of the native ... ...

    Abstract Cells have evolved sophisticated molecular control systems to maximize the efficiency of the folding process. However, any subtle alteration of the environment or the protein can lead to misfolding or affect the conformational plasticity of the native states. It has been widely demonstrated that misfolding and/or conformational instability are the underlying mechanisms of several rare disorders caused by enzymatic deficits. In fact, disease-causing mutations often lead to the substitution of amino acids that are crucial for the achievement of a folded conformation, or play a role on the equilibrium between native-state conformers. One of the promising approaches to treat conformational disorders is the use of pharmacological chaperones (PCs), small molecules that specifically bind a target protein and stabilize a functional fold, thus increasing the amount of functionally active enzyme. Molecules acting as PCs are usually coenzymes, substrate analogues behaving as competitive inhibitors, or allosteric modulators. In this review, the general features of PCs are described, along with three examples of diseases (Gaucher disease, Phenylketonuria, and Primary Hyperoxaluria) in which this approach is currently under study at preclinical and/or clinical level.
    Keywords misfolding ; parmacological chaperones ; gaucher disease ; phenylketonuria ; primary hyperoxaluria ; Biochemistry ; QD415-436 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher IMR Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Molecular and Cellular Studies Reveal Folding Defects of Human Ornithine Aminotransferase Variants Associated With Gyrate Atrophy of the Choroid and Retina

    Riccardo Montioli / Giada Sgaravizzi / Maria Andrea Desbats / Silvia Grottelli / Carla Borri Voltattorni / Leonardo Salviati / Barbara Cellini

    Frontiers in Molecular Biosciences, Vol

    2021  Volume 8

    Abstract: The deficit of human ornithine aminotransferase (hOAT) is responsible for gyrate atrophy (GA), a rare recessive inherited disorder. Although more than 60 disease-associated mutations have been identified to date, the molecular mechanisms explaining how ... ...

    Abstract The deficit of human ornithine aminotransferase (hOAT) is responsible for gyrate atrophy (GA), a rare recessive inherited disorder. Although more than 60 disease-associated mutations have been identified to date, the molecular mechanisms explaining how each mutation leads to the deficit of OAT are mostly unknown. To fill this gap, we considered six representative missense mutations present in homozygous patients concerning residues spread over the hOAT structure. E. coli expression, spectroscopic, kinetic and bioinformatic analyses, reveal that the R154L and G237D mutations induce a catalytic more than a folding defect, the Q90E and R271K mutations mainly impact folding efficiency, while the E318K and C394Y mutations give rise to both folding and catalytic defects. In a human cellular model of disease folding-defective variants, although at a different extent, display reduced protein levels and/or specific activity, due to increased aggregation and/or degradation propensity. The supplementation with Vitamin B6, to mimic a treatment strategy available for GA patients, does not significantly improve the expression/activity of folding-defective variants, in contrast with the clinical responsiveness of patients bearing the E318K mutation. Thus, we speculate that the action of vitamin B6 could be also independent of hOAT. Overall, these data represent a further effort toward a comprehensive analysis of GA pathogenesis at molecular and cellular level, with important relapses for the improvement of genotype/phenotype correlations and the development of novel treatments.
    Keywords gyrate atrophy ; pyridoxal phosphate ; ornithine aminotransferase ; pathogenic variant ; vitamin B6 ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Acetamidine-Based iNOS Inhibitors as Molecular Tools to Counteract Inflammation in BV2 Microglial Cells

    Silvia Grottelli / Rosa Amoroso / Lara Macchioni / Fiorella D’Onofrio / Katia Fettucciari / Ilaria Bellezza / Cristina Maccallini

    Molecules, Vol 25, Iss 2646, p

    2020  Volume 2646

    Abstract: Neurodegenerative diseases are associated with increased levels of nitric oxide (NO) mainly produced by microglial cells through inducible nitric oxide synthase (iNOS) whose expression is induced by inflammatory stimuli. NO can both exert cytotoxic ... ...

    Abstract Neurodegenerative diseases are associated with increased levels of nitric oxide (NO) mainly produced by microglial cells through inducible nitric oxide synthase (iNOS) whose expression is induced by inflammatory stimuli. NO can both exert cytotoxic functions and induce a metabolic switch by inhibiting oxidative phosphorylation and upregulating glycolytic flux. Here, we investigated whether two newly synthesized acetamidine based iNOS inhibitors, namely CM292 and CM544, could inhibit lipopolysaccharide (LPS)-induced BV2 microglial cell activation, focusing on both inflammatory and metabolic profiles. We found that CM292 and CM544, without affecting iNOS protein expression, reduced NO production and reverted LPS-induced inflammatory and cytotoxic response. Furthermore, in the presence of the inflammatory stimulus, both the inhibitors increased the expression of glycolytic enzymes. In particular, CM292 significantly reduced nuclear accumulation of pyruvate kinase M2, increased mitochondrial membrane potential and oxygen consumption rate, and augmented the expression of pyruvate dehydrogenase, pointing to a metabolic switch toward oxidative phosphorylation. These data confirm the role played by NO in the connection between cell bioenergetics profile and inflammation, and suggest the potential usefulness of iNOS inhibitors in redirecting microglia from detrimental to pro-regenerative phenotype.
    Keywords acetamidine ; iNOS inhibitor ; nitric oxide ; inflammation ; pyruvate kinase M2 ; glycolytic enzymes ; Organic chemistry ; QD241-441
    Subject code 570
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Dimerization Drives Proper Folding of Human Alanine:Glyoxylate Aminotransferase But Is Dispensable for Peroxisomal Targeting

    Mirco Dindo / Giulia Ambrosini / Elisa Oppici / Angel L. Pey / Peter J. O’Toole / Joanne L. Marrison / Ian E. G. Morrison / Elena Butturini / Silvia Grottelli / Claudio Costantini / Barbara Cellini

    Journal of Personalized Medicine, Vol 11, Iss 273, p

    2021  Volume 273

    Abstract: Peroxisomal matrix proteins are transported into peroxisomes in a fully-folded state, but whether multimeric proteins are imported as monomers or oligomers is still disputed. Here, we used alanine:glyoxylate aminotransferase (AGT), a homodimeric ... ...

    Abstract Peroxisomal matrix proteins are transported into peroxisomes in a fully-folded state, but whether multimeric proteins are imported as monomers or oligomers is still disputed. Here, we used alanine:glyoxylate aminotransferase (AGT), a homodimeric pyridoxal 5′-phosphate (PLP)-dependent enzyme, whose deficit causes primary hyperoxaluria type I (PH1), as a model protein and compared the intracellular behavior and peroxisomal import of native dimeric and artificial monomeric forms. Monomerization strongly reduces AGT intracellular stability and increases its aggregation/degradation propensity. In addition, monomers are partly retained in the cytosol. To assess possible differences in import kinetics, we engineered AGT to allow binding of a membrane-permeable dye and followed its intracellular trafficking without interfering with its biochemical properties. By fluorescence recovery after photobleaching, we measured the import rate in live cells. Dimeric and monomeric AGT displayed a similar import rate, suggesting that the oligomeric state per se does not influence import kinetics. However, when dimerization is compromised, monomers are prone to misfolding events that can prevent peroxisomal import, a finding crucial to predicting the consequences of PH1-causing mutations that destabilize the dimer. Treatment with pyridoxine of cells expressing monomeric AGT promotes dimerization and folding, thus, demonstrating the chaperone role of PLP. Our data support a model in which dimerization represents a potential key checkpoint in the cytosol at the crossroad between misfolding and correct targeting, a possible general mechanism for other oligomeric peroxisomal proteins.
    Keywords alanine:glyoxylate aminotransferase ; pyridoxal phosphate ; peroxisome ; peroxisomal import ; dimerization ; protein folding ; Medicine ; R
    Subject code 612 ; 570
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: The Role of Cyclo(His-Pro) in Neurodegeneration

    Silvia Grottelli / Ilaria Ferrari / Grazia Pietrini / Matthew J. Peirce / Alba Minelli / Ilaria Bellezza

    International Journal of Molecular Sciences, Vol 17, Iss 8, p

    2016  Volume 1332

    Abstract: Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, ... ...

    Abstract Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function.
    Keywords oxidative stress ; endoplasmic reticulum stress ; neuroinflammation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2016-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

    Vinitha N. Ragavan / Pramod C. Nair / Natalia Jarzebska / Ramcharan Singh Angom / Luana Ruta / Elisa Bianconi / Silvia Grottelli / Natalia D. Tararova / Daniel Ryazanskiy / Steven R. Lentz / Sara Tommasi / Jens Martens-Lobenhoffer / Toshiko Suzuki-Yamamoto / Masumi Kimoto / Elena Rubets / Sarah Chau / Yingjie Chen / Xinli Hu / Nadine Bernhardt /
    Peter M. Spieth / Norbert Weiss / Stefan R. Bornstein / Debabrata Mukhopadhyay / Stefanie M. Bode-Böger / Renke Maas / Ying Wang / Antonio Macchiarulo / Arduino A. Mangoni / Barbara Cellini / Roman N. Rodionov

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 16

    Abstract: Abstract Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA ...

    Abstract Abstract Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.
    Keywords Science ; Q
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: α-Tocopheryl succinate pre-treatment attenuates quinone toxicity in prostate cancer PC3 cells

    Bellezza, Ilaria / Alba Minelli / Anna Lisa Mierla / Leonardo Gatticchi / Silvia Grottelli

    Gene. 2014 Apr. 10, v. 539

    2014  

    Abstract: α-Tocopheryl succinate is one of the most effective analogues of vitamin E for inhibiting cell proliferation and inducing cell death in a variety of cancerous cell lines while sparing normal cells or tissues. αTocopheryl succinate inhibits oxidative ... ...

    Abstract α-Tocopheryl succinate is one of the most effective analogues of vitamin E for inhibiting cell proliferation and inducing cell death in a variety of cancerous cell lines while sparing normal cells or tissues. αTocopheryl succinate inhibits oxidative phosphorylation at the level of mitochondrial complexes I and II, thus enhancing reactive oxygen species generation which, in turn, induces the expression of Nrf2-driven antioxidant/detoxifying genes. The cytoprotective role of Nrf2 downstream genes/proteins prompted us to investigate whether and how α-tocopheryl succinate increases resistance of PC3 prostate cancer cells to pro-oxidant damage. A 4h α-tocopheryl succinate pre-treatment increases glutathione intracellular content, indicating that the vitamin E derivative is capable of training the cells to react to an oxidative insult. We found that α-tocopheryl succinate pre-treatment does not enhance paraquat-/hydroquinone-induced cytotoxicity whereas it exhibits an additional/synergistic effect on H2O2-/docetaxel-induced cytotoxicity.While glutathione and heme oxygenase-1 are not involved in α-tocopheryl succinate-induced adaptive response to paraquat, NAD(P)H:quinone oxidoreductase seems to be responsible, at least in part, for the lack of the additional response. Silencing the gene and/or the inhibition of NAD(P)H:quinone oxidoreductase activity counteracts the α-tocopheryl succinate-induced adaptive response. In conclusion, the adaptive response to α-tocopheryl succinate shows that the activation of Nrf2 can promote the survival of cancer cells in an unfavourable environment.
    Keywords alpha-tocopherol ; antioxidants ; cell death ; cell proliferation ; cytotoxicity ; gene silencing ; genes ; glutathione ; heme oxygenase (biliverdin-producing) ; mitochondria ; neoplasm cells ; oxidative phosphorylation ; paraquat ; prostatic neoplasms ; proteins ; reactive oxygen species ; succinic acid ; synergism
    Language English
    Dates of publication 2014-0410
    Size p. 1-7.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2014.02.009
    Database NAL-Catalogue (AGRICOLA)

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  8. Article ; Online: Denervation does not induce muscle atrophy through oxidative stress

    Eva Pigna / Emanuela Greco / Giulio Morozzi / Silvia Grottelli / Alessio Rotini / Alba Minelli / Stefania Fulle / Sergio Adamo / Rosa Mancinelli / Ilaria Bellezza / Viviana Moresi

    European Journal of Translational Myology, Vol 27, Iss

    2017  Volume 1

    Abstract: Denervation leads to the activation of the catabolic pathways, such as the ubiquitin-proteasome and autophagy, resulting in skeletal muscle atrophy and weakness. Furthermore, denervation induces oxidative stress in skeletal muscle, which is thought to ... ...

    Abstract Denervation leads to the activation of the catabolic pathways, such as the ubiquitin-proteasome and autophagy, resulting in skeletal muscle atrophy and weakness. Furthermore, denervation induces oxidative stress in skeletal muscle, which is thought to contribute to the induction of skeletal muscle atrophy. Several muscle diseases are characterized by denervation, but the molecular pathways contributing to muscle atrophy have been only partially described. Our study delineates the kinetics of activation of oxidative stress response in skeletal muscle following denervation. Despite the denervation-dependent induction of oxidative stress in skeletal muscle, treatments with anti-oxidant drugs do not prevent the reduction of muscle mass. Our results indicate that, although oxidative stress may contribute to the activation of the response to denervation, it is not responsible by itself of oxidative damage or neurogenic muscle atrophy.
    Keywords Denervation ; Oxidative stress ; Antioxidant drug ; Neurogenic muscle atrophy ; Medicine ; R ; Human anatomy ; QM1-695
    Language English
    Publishing date 2017-03-01T00:00:00Z
    Publisher PAGEPress Publications
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article: Neuroinflammation and endoplasmic reticulum stress are coregulated by cyclo(His-Pro) to prevent LPS neurotoxicity

    Bellezza, Ilaria / Alba Minelli / Anna Lisa Mierla / Erika Fornasari / Gianluigi Cardinali / Ivana Cacciatore / Luca Roscini / Silvia Grottelli

    international journal of biochemistry & cell biology. 2014 June, v. 51

    2014  

    Abstract: Many neurological and neurodegenerative diseases are associated with oxidative stress and glial inflammation, all related to endoplasmic reticulum stress. Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts cytoprotection by interfering with the ...

    Abstract Many neurological and neurodegenerative diseases are associated with oxidative stress and glial inflammation, all related to endoplasmic reticulum stress. Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts cytoprotection by interfering with the Nrf2–NF-κB systems, the former presiding the antioxidant and the latter the pro-inflammatory cellular response. Here we investigated whether the cyclic dipeptide inhibits glial inflammation thus reducing the detrimental effect of inflammatory neurotoxins on neurons. We found that systemic administration of cyclo(His-Pro) exerts in vivo anti-inflammatory effects in the central nervous system by down-regulating hepatic and cerebral TNFα expression thereby counteracting LPS-induced gliosis. Mechanistic studies indicated that the cyclic dipeptide-mediated effects are achieved through the activation of Nrf2-driven antioxidant response and the inhibition of the pro-inflammatory NF-κB pathway. Moreover, by up-regulating Bip, cyclo(His-Pro) increases the ER stress sensitivity and triggers the unfolded protein response to alleviate the ER stress. These results unveil a novel potential therapeutic use of cyclo(His-Pro) against neuroinflammatory-related diseases and we might now consider its potential anti-inflammatory role in other neuropathological conditions.
    Keywords anti-inflammatory activity ; antioxidant activity ; antioxidants ; central nervous system ; endoplasmic reticulum stress ; inflammation ; neurodegenerative diseases ; neurons ; neurotoxicity ; neurotoxins ; oxidative stress ; therapeutics ; transcription factor NF-kappa B ; tumor necrosis factor-alpha ; unfolded protein response
    Language English
    Dates of publication 2014-06
    Size p. 159-169.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 1228429-4
    ISSN 1878-5875 ; 1357-2725
    ISSN (online) 1878-5875
    ISSN 1357-2725
    DOI 10.1016/j.biocel.2014.03.023
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