Physiological roles of glutathione in organism

Glutation (γ-glutamil-cisteinilglicin, GSH) je tripeptid prisutan u velikim količinama u svim stanicama sisavaca. Sintetizira se u stanicama svih organa, posebno u jetri. Najveća količina nalazi se u citosolu, mitohondriju i ER. Služi kao antioksidans i detoksifikator u mnogim procesima metabolizma i regulira stanična zbivanja. Postoji u dva oblika-reduciranom (GSH) koji može oksidirati do disulfida (GSSG), a njihov omjer određuje redoks stanje stanice koje je bitan posrednik u više procesa. U ovom radu obrađuju se uloge GSH kao regulatora staničnog redoks statusa u kontroli transkripcijskih faktora i imunološkog odgovora te kao kofaktora u sintezi proupalnih posrednika ili spoja s NO. Smanjenje razine GSH u uvjetima oksidacijskog stresa aktivira transkripcijske faktore NF-κB i AP-1 koji potiču ekspresiju mnogih proupalnih gena i gena za citokine. U imunološkom sustavu GSH ima dvojaku ulogu: utječe na smanjenje sinteze citokina koji mogu dodatno pojačati oksidacijski stres, a dovoljna količina GSH potrebna je za proliferaciju limfocita T i odgovarajući imunološki odgovor. GSH služi i kao kofaktor u pojedinim koracima sinteze proupalnih posrednika, leukotriena i prostaglandina, koje kataliziraju membranski enzimi porodice GSH S-transferaza imena MAPEG. NO se može spojiti s GSH pri čemu nastaje S-nitrozoglutation (GSNO) koji može posttranslacijskom modifikacijom preko S-tiolacije ili S-glutationilacije utjecati na aktivnost proteina i time inhibirati apoptozu ili utjecati na redoks stanje stanice.Glutathione (γ-glutamylcysteinylglycine, GSH) is a tripeptid present in large levels in all mammalian tissues. It is synthetized within the cells of all organs, especially in the liver. The largest levels of GSH are present in cytosol, mitochondria and ER. GSH serves as antioxidant, detoxifying agent in a number of metabolism processes and it modulates cell events. There are two forms of GSH: reduced form (GSH) which can oxidize to disulphide (GSSG), GSH/GSSG ratio determines redox state of cells which is important factor in many processes. This review explaines roles of GSH as a regulator of cellular processes in a modulation of transcriptional factors and immune responses and, also, as a cofactor in proinflammatory mediators synthesis and NO-adduct formation. In conditions of oxidative stress, a decrease in GSH levels activates transcriptional factors NF-κB i AP-1 which then activate pro-inflammatory genes and cytokine genes expression. GSH has a double role in the immune system: it affects the decrease in cytokine synthesis which can enhance oxidative stress and, also, adequate levels of GSH are essential for T lymphocyte proliferation and successful immune response. In the synthesis of pro-inflammatory mediators, leukotrienes and prostaglandins, GSH serves as a cofactor in some of the steps catalyzed by special GSH-S transferase membrane-bound enzymes called MAPEG. NO can form an adduct with GSH forming S-nitrosoglutathione (GSNO) which by posttranslational modification through Sthiolation and S-glutathionilation can modify protein activity and additionally apoptosis inhibition or cell redox state

Glutationilacija – regulacijska uloga glutationa u fiziološkim procesima

Glutathione (γ-glutamyl-cysteinyl-glycine) is an intracellular thiol molecule and a potent antioxidant that participates in the toxic metabolism phase II biotransformation of xenobiotics. It can bind to a variety of proteins in a process known as glutathionylation. Protein glutathionylation is now recognised as one of important posttranslational regulatory mechanisms in cell and tissue physiology. Direct and indirect regulatory roles in physiological processes include glutathionylation of major transcriptional factors, eicosanoids, cytokines, and nitric oxide (NO). This review looks into these regulatory mechanisms through examples of glutathione regulation in apoptosis, vascularisation, metabolic processes, mitochondrial integrity, immune system, and neural physiology. The focus is on the physiological roles of glutathione beyond biotransformational metabolism.Glutation (γ-glutamil-cisteinil-glicin) stanični je tripeptid, tiolni spoj i jaki antioksidans koji sudjeluje u metabolizmu otrova i biotransformaciji ksenobiotika faze II. Može se vezati na različite proteine u procesu poznatom pod nazivom glutationilacija. Proteinska glutationilacija dokazano je jedan od važnih posttranslacijskih upravljačkih mehanizama u fiziologiji stanica i tkiva. Izravne i neizravne upravljačke uloge u fiziološkim procesima uključuju glutationilaciju glavnih transkripcijskih faktora, eikozanoida, citokina i dušikova oksida (NO). U ovom se preglednom radu razmatraju navedeni upravljački mehanizmi na primjerima regulacije glutationom u apoptozi, vaskularizaciji, metaboličkim procesima, mitohondrijskom integritetu, imunološkom sustavu i fiziologiji živčanog sustava. Težište je rada na novim opisanim fiziološkim ulogama glutationa, pored uobičajeno opisane uloge u biotransformacijskom metabolizmu

Physiological roles of glutathione in organism

Glutation (γ-glutamil-cisteinilglicin, GSH) je tripeptid prisutan u velikim količinama u svim stanicama sisavaca. Sintetizira se u stanicama svih organa, posebno u jetri. Najveća količina nalazi se u citosolu, mitohondriju i ER. Služi kao antioksidans i detoksifikator u mnogim procesima metabolizma i regulira stanična zbivanja. Postoji u dva oblika-reduciranom (GSH) koji može oksidirati do disulfida (GSSG), a njihov omjer određuje redoks stanje stanice koje je bitan posrednik u više procesa. U ovom radu obrađuju se uloge GSH kao regulatora staničnog redoks statusa u kontroli transkripcijskih faktora i imunološkog odgovora te kao kofaktora u sintezi proupalnih posrednika ili spoja s NO. Smanjenje razine GSH u uvjetima oksidacijskog stresa aktivira transkripcijske faktore NF-κB i AP-1 koji potiču ekspresiju mnogih proupalnih gena i gena za citokine. U imunološkom sustavu GSH ima dvojaku ulogu: utječe na smanjenje sinteze citokina koji mogu dodatno pojačati oksidacijski stres, a dovoljna količina GSH potrebna je za proliferaciju limfocita T i odgovarajući imunološki odgovor. GSH služi i kao kofaktor u pojedinim koracima sinteze proupalnih posrednika, leukotriena i prostaglandina, koje kataliziraju membranski enzimi porodice GSH S-transferaza imena MAPEG. NO se može spojiti s GSH pri čemu nastaje S-nitrozoglutation (GSNO) koji može posttranslacijskom modifikacijom preko S-tiolacije ili S-glutationilacije utjecati na aktivnost proteina i time inhibirati apoptozu ili utjecati na redoks stanje stanice.Glutathione (γ-glutamylcysteinylglycine, GSH) is a tripeptid present in large levels in all mammalian tissues. It is synthetized within the cells of all organs, especially in the liver. The largest levels of GSH are present in cytosol, mitochondria and ER. GSH serves as antioxidant, detoxifying agent in a number of metabolism processes and it modulates cell events. There are two forms of GSH: reduced form (GSH) which can oxidize to disulphide (GSSG), GSH/GSSG ratio determines redox state of cells which is important factor in many processes. This review explaines roles of GSH as a regulator of cellular processes in a modulation of transcriptional factors and immune responses and, also, as a cofactor in proinflammatory mediators synthesis and NO-adduct formation. In conditions of oxidative stress, a decrease in GSH levels activates transcriptional factors NF-κB i AP-1 which then activate pro-inflammatory genes and cytokine genes expression. GSH has a double role in the immune system: it affects the decrease in cytokine synthesis which can enhance oxidative stress and, also, adequate levels of GSH are essential for T lymphocyte proliferation and successful immune response. In the synthesis of pro-inflammatory mediators, leukotrienes and prostaglandins, GSH serves as a cofactor in some of the steps catalyzed by special GSH-S transferase membrane-bound enzymes called MAPEG. NO can form an adduct with GSH forming S-nitrosoglutathione (GSNO) which by posttranslational modification through Sthiolation and S-glutathionilation can modify protein activity and additionally apoptosis inhibition or cell redox state

Physiological roles of glutathione in organism

Glutation (γ-glutamil-cisteinilglicin, GSH) je tripeptid prisutan u velikim količinama u svim stanicama sisavaca. Sintetizira se u stanicama svih organa, posebno u jetri. Najveća količina nalazi se u citosolu, mitohondriju i ER. Služi kao antioksidans i detoksifikator u mnogim procesima metabolizma i regulira stanična zbivanja. Postoji u dva oblika-reduciranom (GSH) koji može oksidirati do disulfida (GSSG), a njihov omjer određuje redoks stanje stanice koje je bitan posrednik u više procesa. U ovom radu obrađuju se uloge GSH kao regulatora staničnog redoks statusa u kontroli transkripcijskih faktora i imunološkog odgovora te kao kofaktora u sintezi proupalnih posrednika ili spoja s NO. Smanjenje razine GSH u uvjetima oksidacijskog stresa aktivira transkripcijske faktore NF-κB i AP-1 koji potiču ekspresiju mnogih proupalnih gena i gena za citokine. U imunološkom sustavu GSH ima dvojaku ulogu: utječe na smanjenje sinteze citokina koji mogu dodatno pojačati oksidacijski stres, a dovoljna količina GSH potrebna je za proliferaciju limfocita T i odgovarajući imunološki odgovor. GSH služi i kao kofaktor u pojedinim koracima sinteze proupalnih posrednika, leukotriena i prostaglandina, koje kataliziraju membranski enzimi porodice GSH S-transferaza imena MAPEG. NO se može spojiti s GSH pri čemu nastaje S-nitrozoglutation (GSNO) koji može posttranslacijskom modifikacijom preko S-tiolacije ili S-glutationilacije utjecati na aktivnost proteina i time inhibirati apoptozu ili utjecati na redoks stanje stanice.Glutathione (γ-glutamylcysteinylglycine, GSH) is a tripeptid present in large levels in all mammalian tissues. It is synthetized within the cells of all organs, especially in the liver. The largest levels of GSH are present in cytosol, mitochondria and ER. GSH serves as antioxidant, detoxifying agent in a number of metabolism processes and it modulates cell events. There are two forms of GSH: reduced form (GSH) which can oxidize to disulphide (GSSG), GSH/GSSG ratio determines redox state of cells which is important factor in many processes. This review explaines roles of GSH as a regulator of cellular processes in a modulation of transcriptional factors and immune responses and, also, as a cofactor in proinflammatory mediators synthesis and NO-adduct formation. In conditions of oxidative stress, a decrease in GSH levels activates transcriptional factors NF-κB i AP-1 which then activate pro-inflammatory genes and cytokine genes expression. GSH has a double role in the immune system: it affects the decrease in cytokine synthesis which can enhance oxidative stress and, also, adequate levels of GSH are essential for T lymphocyte proliferation and successful immune response. In the synthesis of pro-inflammatory mediators, leukotrienes and prostaglandins, GSH serves as a cofactor in some of the steps catalyzed by special GSH-S transferase membrane-bound enzymes called MAPEG. NO can form an adduct with GSH forming S-nitrosoglutathione (GSNO) which by posttranslational modification through Sthiolation and S-glutathionilation can modify protein activity and additionally apoptosis inhibition or cell redox state

The Dual Nature of the Antiepileptic Drug Valproic Acid, With Possible Beneficial Effects in Alzheimer’s Disease

Valproic acid (VPA) is a short fatty acid with strong anticonvulsant properties. It has diverse effects in different tissues with opposing mechanisms of physiological action. Due to the effects on energy, fatty acid, and cholesterol metabolism, it may be a risk factor for the development of diabetes with its associated complications of atherosclerosis, weight gain, hypertension, insulin resistance and other complications. Its negative effects on the endocrine system can have severe health consequences, especially in the female population.VPA produces proinflammatory and proapoptotic effects in the liver and anti-inflammatory and antiapoptotic effects in the central nervous system. It also causes abnormalities in lipid and cholesterol transport in the liver and the reproductive organs, while in neural stem cells it decreases cholesterol accumulation and helps neural growth and differentiation. However, in the CNS it has some beneficial effects which are proposed to be important in Alzheimer’s disease (AD). In AD mouse models, VPA exerted antiapoptotic effects and the expression of transcription factors that promote neurite growth. Most of the adverse pathogenic actions or beneficial molecular effects are not fully understood. We present an overview and comparison of the different properties of VPA and their effects on estrogen and cholesterol metabolism, lipid transport, Alzheimer’s disease, and on the physiology of the liver, reproductive organs, and neuronsfrom in vitro and in vivo (in animal models and patients) studies

Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation

Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis that retromer impairment may be involved in the pathogenesis of NPC and may contribute to increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis observed in NPC disease. Using NPC1-null cells, primary mouse NPC1-deficient neurons and NPC1-deficient mice (BALB/cNctr-Npc1m1N), we show that retromer function is impaired in NPC. This is manifested by altered transport of the retromer core components Vps26, Vps35 and/or retromer receptor sorLA and by retromer accumulation in neuronal processes, such as within axonal swellings. Changes in retromer distribution in NPC1 mouse brains were observed already at the presymptomatic stage (at 4-weeks of age), indicating that the retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Furthermore, we show that cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverts retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. Thus, we characterized retromer dysfunction in NPC and propose that the rescue of retromer impairment may represent a novel therapeutic approach against NPC

Structure and function of cancer-related developmentally regulated GTP-binding protein 1 (DRG1) is conserved between sponges and humans

Cancer is a disease caused by errors within the multicellular system and it represents a major health issue in multicellular organisms. Although cancer research has advanced substantially, new approaches focusing on fundamental aspects of cancer origin and mechanisms of spreading are necessary. Comparative genomic studies have shown that most genes linked to human cancer emerged during the early evolution of Metazoa. Thus, basal animals without true tissues and organs, such as sponges (Porifera), might be an innovative model system for understanding the molecular mechanisms of proteins involved in cancer biology. One of these proteins is developmentally regulated GTP- binding protein 1 (DRG1), a GTPase stabilized by interaction with DRG family regulatory protein 1 (DFRP1). This study reveals a high evolutionary conservation of DRG1 gene/protein in metazoans. Our biochemical analysis and structural predictions show that both recombinant sponge and human DRG1 are predominantly monomers that form complexes with DFRP1 and bind non-specifically to RNA and DNA. We demonstrate the conservation of sponge and human DRG1 biological features, including intracellular localization and DRG1:DFRP1 binding, function of DRG1 in α-tubulin dynamics, and its role in cancer biology demonstrated by increased proliferation, migration and colonization in human cancer cells. These results suggest that the ancestor of all Metazoa already possessed DRG1 that is structurally and functionally similar to the human DRG1, even before the development of real tissues or tumors, indicating an important function of DRG1 in fundamental cellular pathways

Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation

Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis that retromer impairment may be involved in the pathogenesis of NPC and may contribute to increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis observed in NPC disease. Using NPC1-null cells, primary mouse NPC1-deficient neurons and NPC1-deficient mice (BALB/cNctr-Npc1m1N), we show that retromer function is impaired in NPC. This is manifested by altered transport of the retromer core components Vps26, Vps35 and/or retromer receptor sorLA and by retromer accumulation in neuronal processes, such as within axonal swellings. Changes in retromer distribution in NPC1 mouse brains were observed already at the presymptomatic stage (at 4-weeks of age), indicating that the retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Furthermore, we show that cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverts retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. Thus, we characterized retromer dysfunction in NPC and propose that the rescue of retromer impairment may represent a novel therapeutic approach against NPC