Abstract
Selenoprotein P (SeP; encoded by SELENOP) is selenium (Se)-rich plasma protein that is mainly produced in the liver. SeP functions as a Se-transport protein to deliver Se from the liver to ...other tissues, such as the brain and testis. The protein plays a pivotal role in Se metabolism and antioxidative defense, and it has been identified as a ‘hepatokine’ that causes insulin resistance in type 2 diabetes. SeP levels are increased in type 2 diabetes patients, and excess SeP impairs insulin signalling, promoting insulin resistance. Furthermore, increased levels of SeP disturb the functioning of pancreatic β cells and inhibit insulin secretion. This review focuses on the biological function of SeP and the molecular mechanisms associated with the adverse effects of excess SeP on pancreatic β cells’ function, particularly with respect to redox reactions. Interactions between the liver and pancreas are also discussed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Lipid peroxidation and its products have been investigated extensively and their biological importance, particularly in relation to physiological and pathophysiological conditions, has received ...considerable attention. Lipids are oxidized by three distinct mechanisms, i.e., enzymatic oxidation, nonenzymatic, free radical-mediated oxidation, and nonenzymatic, nonradical-mediated oxidation, which respectively yield specific products. Lipid hydroperoxides are the major primary products formed and are reduced to the corresponding hydroxides by antioxidative enzymes such as selenoproteins, and/or undergo secondary oxidation, generating various products with electrophilic properties, such as 4-hydroxy-2-nonenal. Lipid peroxidation induces a loss of fine structure and natural function of lipids, and can produce cytotoxicity and/or novel biological activity. This review broadly discusses the mechanisms of lipid peroxidation and its products, its utility as a biomarker for oxidative stress, the biological effects of lipid peroxidation products, including their action as a mediator of the adaptive response, and the role of the antioxidant system, particularly selenoproteins and vitamin E, in preventing lipid peroxidation and ferroptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Selenoprotein P (encoded by SELENOP) contains the essential trace element selenium in the form of selenocysteine, which is an analog of cysteine that contains selenium instead of sulfur. ...Selenoprotein P is a major selenium-containing protein in human plasma and is mainly synthesized in the liver. It functions as a selenium-transporter to maintain antioxidative selenoenzymes in several tissues, such as the brain and testis, and plays a pivotal role in selenium-metabolism and antioxidative defense. A decrease of selenoprotein P and selenoproteins causes various dysfunctions related to oxidative stress. On the other hand, recent studies indicate that excess selenoprotein P exacerbates glucose metabolism and promotes type 2 diabetes. This review focuses on the biological functions of selenoprotein P, particularly its role in selenium-metabolism and antioxidative defense. Furthermore, the effects of excess selenoprotein P on glucose metabolism, and resulting diseases are described. The development of a therapeutic agent that targets excess selenoprotein P is discussed.
Selenoprotein P (SELENOP) is selenium (Se)-containing protein in plasma, which is primarily produced in the liver. The “P” in SELENOP originated from the presence in plasma. SELENOP contains ...selenocysteine, a cysteine analog containing Se instead of sulfur. SELENOP is a multi-functional protein to reduce phospholipid hydroperoxides and to deliver Se from the liver to other tissues, such as those of the brain and testis, playing a pivotal role in Se metabolism and antioxidative defense. Decrease in SELENOP causes various dysfunctions related to Se deficiency and oxidative stress, while excessive SELENOP causes insulin resistance. This review focuses on the Se transport system of SELENOP, particularly its molecular mechanism and physiological role in Se metabolism. Furthermore, the chemical form of Se and its biological meaning is discussed.
Drug lag, recently discussed extensively in Japan, can be divided into two phases: clinical development time and application review time. The former factor is still an important problem that might be ...improved by promoting multi-regional clinical trials and considering the results from other similar populations with Japanese, such as Koreans and Chinese. In this review, we compare the allelic or genotype frequencies of 30 relatively common functional alleles mainly between Eastern Asians and Europeans as well as among 3 major populations in Eastern Asian countries, Japan, Korea, and China, in 12 pharmacokinetics (PK)/pharmacodynamics (PD)-related genes; CYP2C9 (*2 and *3), CYP2C19 (*2, *3 and *17), 13 CYP2D6 haplotypes including *4, *5 and *10, CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5, *6 and *7), GSTM1 and GSTT1 null genotypes, SLCO1B1 521T>C, ABCG2 421C>A, and HLA-A*31:01 and HLA-B* 58:01. In this review, differences in allele frequencies (AFs) or genotype frequencies (GFs) less than 0.1 (in the cases of highest AF (GF) >0.1) or less than 0.05 (in the cases of lowest AF (GF) <0.1) were regarded as similar. Between Eastern Asians and Europeans, AFs (or GFs) are regarded as being different for many alleles such as CYP2C9 (*2), CYP2C19 (*2, *3 and *17), CYP2D6 (*4 and *10), CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5*7), GSTT1 null and ABCG2 421C>A. Among the 3 Eastern Asian populations, however, only AFs of CYP2C19*3, CYP2D6*10, HLA-A*31:01 and HLA- B*58:01 are regarded as dissimilar. For CYP2C19*3, the total functional impact on CYP2C19 could be small if the frequencies of the two null alleles CYP2C19*2 and *3 are combined. Regarding CYP2D6*10, frequency difference over 0.1 is observed only between Japanese and Chinese (0.147). Although environmental factors should be considered for PK/PD differences, we could propose that among Japan, Korea, and China, genetic differences are very small for the analyzed common PK-related gene polymorphisms. On the other hand, AFs of the two HLA alleles important for cutaneous adverse drug reactions are diverse even among Eastern Asians and thus should be taken into account.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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Abstract
The essential trace element selenium plays a significant role in redox homeostasis in the human body. Selenium is very reactive and has a potent toxicity; however, the ...living body cleverly utilizes its reactivity for redox reactions. The biological function of selenium is mainly mediated by selenoproteins, which contain selenocysteine, a cysteine analogue that possesses selenium instead of sulphur. Twenty-five types of human selenoproteins have been identified, including glutathione peroxidase (GPX; for the reduction of hydrogen peroxide and lipid hydroperoxide) and thioredoxin reductase (for redox regulation). Selenoprotein P (SELENOP), which is a major selenoprotein in the plasma, is mainly synthesized in the liver and secreted into the plasma. As a multifunctional protein with selenium-transporting activity, GPX-like activity, and metal-binding properties, SELENOP plays a vital role in selenium metabolism and redox regulation. This review focuses on the relationship between selenium metabolism and redox regulation, particularly on the physiological role of selenoproteins and the pathophysiological implications of its disorder. Furthermore, the significant roles of selenium in infectious diseases and its utility for phylaxis are discussed.
Selenoprotein P (SeP) is one of the 25 human selenocysteine (Sec)-containing proteins, and is generally thought to function as a plasma carrier of the trace element selenium in the body. Recent ...studies, however, indicate unsuspected pivotal roles of SeP in human diseases, particularly in type 2 diabetes mellitus (T2DM) and pulmonary arterial hypertension (PAH). In this review, we will summarize the characteristics of SeP and recent advances in the field, especially focusing on the emerging roles of SeP in pathophysiological conditions. We will also discuss potential medical/pharmaceutical applications targeting SeP.
Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility ...to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage, cells express peroxidases, ...which are antioxidant enzymes that catalyze the reduction of oxidized biomolecules. Glutathione peroxidase 4 (GPX4) is the major hydroperoxidase specifically responsible for reducing lipid peroxides; this homeostatic mechanism is essential, and its inhibition causes a unique type of lytic cell death, ferroptosis. The mechanism(s) that lead to cell lysis in ferroptosis, however, are unclear. We report that the lipid peroxides formed during ferroptosis accumulate preferentially at the plasma membrane. Oxidation of surface membrane lipids increased tension on the plasma membrane and led to the activation of Piezo1 and TRP channels. Oxidized membranes thus became permeable to cations, ultimately leading to the gain of cellular Na+ and Ca2+ concomitant with loss of K+. These effects were reduced by deletion of Piezo1 and completely inhibited by blocking cation channel conductance with ruthenium red or 2-aminoethoxydiphenyl borate (2-APB). We also found that the oxidation of lipids depressed the activity of the Na+/K+-ATPase, exacerbating the dissipation of monovalent cation gradients. Preventing the changes in cation content attenuated ferroptosis. Altogether, our study establishes that increased membrane permeability to cations is a critical step in the execution of ferroptosis and identifies Piezo1, TRP channels, and the Na+/K+-ATPase as targets/effectors of this type of cell death.
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•Lipid peroxidation increases plasma membrane tension and opens Piezo1•Piezo1 and TRP channels cooperatively promote ferroptosis by facilitating cation flux•Collapse of transmembrane cation gradients is magnified by Na+/K+-ATPase inhibition•Blocking sodium influx and/or potassium efflux suppresses ferroptosis
Hirata et al. report that peroxidation of lipids increases plasma membrane tension and leads to the activation of mechanosensitive cation channels including Piezo1. Gating of these channels induces loss of K+ and gain of Na+ that promote ferroptosis. These findings demonstrate key roles of mechanosensing channels in the execution of ferroptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP