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  • 刊频： Thirty six no. a year, 2013-
  • NLM标题： Antioxid Redox Signal
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  • 1.

    【2hr】Single-Cell Transcriptomics of Human Oocytes: Environment-Driven Metabolic Competition and Compensatory Mechanisms During Oocyte Maturation

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    机译 人类卵母细胞的单细胞转录组学：在卵母细胞成熟过程中环境驱动的代谢竞争和补偿机制。
    摘要：Aims: The mechanisms coordinating maturation with an environment-driven metabolic shift, a critical step in determining the developmental potential of human in vitro maturation (IVM) oocytes, remain to be elucidated. Here we explored the key genes regulating human oocyte maturation using single-cell RNA sequencing and illuminated the compensatory mechanism from a metabolic perspective by analyzing gene expression.Results: Three key genes that encode CoA-related enzymes were screened from the RNA sequencing data. Two of them, ACAT1 and HADHA, were closely related to the regulation of substrate production in the Krebs cycle. Dysfunction of the Krebs cycle was induced by decreases in the activity of specific enzymes. Furthermore, the activator of these enzymes, the calcium concentration, was also decreased because of the failure of influx of exogenous calcium. Although release of endogenous calcium from the endoplasmic reticulum and mitochondria met the requirement for maturation, excessive release resulted in aneuploidy and developmental incompetence. High nicotinamide nucleotide transhydrogenase expression induced NADPH dehydrogenation to compensate for the NADH shortage resulting from the dysfunction of the Krebs cycle. Importantly, high NADP+ levels activated DPYD to enhance the repair of DNA double-strand breaks to maintain euploidy.Innovation: The present study shows for the first time that exposure to the in vitro environment can lead to the decline of energy metabolism in human oocytes during maturation but that a compensatory action maintains their developmental competence.Conclusion: In vitro maturation of human oocytes is mediated through a cascade of competing and compensatory actions driven by genes encoding enzymes.
  • 2.

    【2hr】Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses

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    机译 细胞调节和癌症生物学中的脯氨酸代谢：最新进展和假设
    • 作者：James M. Phang
    • 刊名：Antioxidants Redox Signaling
    • 2019年第4期
    摘要：Significance: It is increasingly clear that proline metabolism plays an important role in metabolic reprogramming, not only in cancer but also in related fields such as aging, senescence, and development. Although first focused on proline catabolism, recent studies from a number of laboratories have emphasized the regulatory effects of proline synthesis and proline cycling.Recent Advances: Although proline dehydrogenase/proline oxidase (PRODH/POX) has been known as a tumor protein 53 (P53)-activated source of redox signaling for initiating apoptosis and autophagy, senescence has been added to the responses. On the biosynthetic side, two well-recognized oncogenes, c-MYC and phosphoinositide 3-kinase (PI3K), markedly upregulate enzymes of proline synthesis; mechanisms affected include augmented redox cycling and maintenance of pyridine nucleotides. The reprogramming has been shown to shift in clonogenesis and/or metastasis.Critical Issues: Although PRODH/POX generates reactive oxygen species (ROS) for signaling, the cellular endpoint is variable and dependent on metabolic context; the switches for these responses remain unknown. On the synthetic side, the enzymes require more complete characterization in various cancers, and demonstration of coupling of proline metabolites to other pathways may require studies of protein–protein interactions, membrane transporters, and shuttles.Future Directions: The proline metabolic axis can serve as a scaffold on which a variety of regulatory mechanisms are integrated. Once understood as a central mechanism in cancer metabolism, proline metabolism may be a good target for adjunctive cancer therapy.
  • 3.

    【2hr】Vascular Adhesion Protein-1: A Cell Surface Amine Oxidase in Translation

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    机译 血管粘附蛋白-1：细胞表面胺氧化酶的翻译。
    摘要：Significance: Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that oxidates primary amines in a reaction producing also hydrogen peroxide. VAP-1 on the blood vessel endothelium regulates leukocyte extravasation from the blood into tissues under physiological and pathological conditions.Recent Advances: Inhibition of VAP-1 by neutralizing antibodies and by several novel small-molecule enzyme inhibitors interferes with leukocyte trafficking and alleviates inflammation in many experimental models. Targeting of VAP-1 also shows beneficial effects in several other diseases, such as ischemia/reperfusion, fibrosis, and cancer. Moreover, soluble VAP-1 levels may serve as a new prognostic biomarker in selected diseases.Critical Issues: Understanding the contribution of the enzyme activity-independent and enzyme activity-dependent functions, which often appear to be mediated by the hydrogen peroxide production, in the VAP-1 biology will be crucial. Similarly, there is a pressing need to understand which of the VAP-1 functions are regulated through the modulation of leukocyte trafficking, and what is the role of VAP-1 synthesized in adipose and smooth muscle cells.Future Directions: The specificity and selectivity of new VAP-1 inhibitors, and their value in animal models under therapeutic settings need to be addressed. Results from several programs studying the therapeutic potential of VAP-1 inhibition, which now are in clinical trials, will reveal the relevance of this amine oxidase in humans.
  • 4.

    【2hr】Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes

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    机译 烟酰胺腺嘌呤二核苷酸和相关前体作为与年龄有关的退行性疾病的治疗目标的作用：基本原理，生物化学，药代动力学和结果
    摘要：Significance: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD+ synthesis pathway in mammalian cells. NAD+ can also be produced by the NAD+ salvage pathway.Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline in degenerative disease states and physiological aging.Critical Issues: Results obtained in recent years have shown that NAD+ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. Increased synthesis of NAD+ promotes protective cell responses, further demonstrating that NAD+ is a regulatory molecule associated with several biochemical pathways.Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD+ precursors and improved detection methodologies allowing the administration of specific NAD+ precursors in the context of patients' NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases.
  • 5.

    【2hr】NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase

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    机译 NADPH氧化酶4调节缺血性心力衰竭的炎症：可溶性环氧水解酶的作用
    摘要：
  • 6.

    【2hr】Crosstalk Between Connexin32 and Mitochondrial Apoptotic Signaling Pathway Plays a Pivotal Role in Renal Ischemia Reperfusion-Induced Acute Kidney Injury

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    机译 连接蛋白和线粒体细胞凋亡信号通路之间的串扰在肾脏缺血再灌注引起的急性肾损伤中起关键作用
    摘要：
  • 7.

    【2hr】Transcriptional Regulation by Nrf2

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    机译 Nrf2的转录调控
    摘要：Significance: Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that coordinates the basal and stress-inducible activation of a vast array of cytoprotective genes. Understanding the regulation of Nrf2 activity and downstream pathways has major implications for human health.Recent Advances: Nrf2 regulates the transcription of components of the glutathione and thioredoxin antioxidant systems, as well as enzymes involved in phase I and phase II detoxification of exogenous and endogenous products, NADPH regeneration, and heme metabolism. It therefore represents a crucial regulator of the cellular defense mechanisms against xenobiotic and oxidative stress. In addition to antioxidant responses, Nrf2 is involved in other cellular processes, such as autophagy, intermediary metabolism, stem cell quiescence, and unfolded protein response. Given the wide range of processes that Nrf2 controls, its activity is tightly regulated at multiple levels. Here, we review the different modes of regulation of Nrf2 activity and the current knowledge of Nrf2-mediated transcriptional control.Critical Issues: It is now clear that Nrf2 lies at the center of a complex regulatory network. A full comprehension of the Nrf2 program will require an integrated consideration of all the different factors determining Nrf2 activity.Future Directions: Additional computational and experimental studies are needed to obtain a more dynamic global view of Nrf2-mediated gene regulation. In particular, studies comparing how the Nrf2-dependent network changes from a physiological to a pathological condition can provide insight into mechanisms of disease and instruct new treatment strategies.
  • 8.

    【2hr】Differential Impact of Flavonoids on Redox Modulation, Bioenergetics, and Cell Signaling in Normal and Tumor Cells: A Comprehensive Review

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    机译 黄酮类化合物对正常和肿瘤细胞中氧化还原调节，生物能和细胞信号传导的差异影响：综述。
    摘要：Significance: Flavonoids can interact with multiple molecular targets to elicit their cellular effects, leading to changes in signal transduction, gene expression, and/or metabolism, which can, subsequently, affect the entire cell and organism. Immortalized cell lines, derived from tumors, are routinely employed as a surrogate for mechanistic studies, with the results extrapolated to tissues in vivo.Recent Advances: We review the activities of selected flavonoids on cultured tumor cells derived from various tissues in comparison to corresponding primary cells or tissues in vivo, mainly using quercetin and flavanols (epicatechin and (−)-epigallocatechin gallate) as exemplars. Several studies have indicated that flavonoids could retard cancer progression in vivo in animal models as well as in tumor cell models.Critical Issues: Extrapolation from in vitro and animal models to humans is not straightforward given both the extensive conjugation and complex microbiota-dependent metabolism of flavonoids after consumption, as well as the heterogeneous metabolism of different tumors.Future Directions: Comparison of data from studies on primary cells or in vivo are essential not only to validate results obtained from cultured cell models, but also to highlight whether any differences may be further exploited in the clinical setting for chemoprevention. Tumor cell models can provide a useful mechanistic tool to study the effects of flavonoids, provided that the limitations of each model are understood and taken into account in interpretation of the data.
  • 9.

    【2hr】Long Noncoding RNAs in Diabetes and Diabetic Complications

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    机译 糖尿病和糖尿病并发症中的长非编码RNA
    摘要：Significance: Diabetes is associated with markedly accelerated rates of micro- and macrovascular complications that increase morbidity and mortality. Understanding the molecular mechanisms can promote much needed therapeutics.Recent Advances: Long noncoding RNAs (lncRNAs) are important regulators of gene regulation and cellular function and are emerging as important players in diabetes and its complications. There are number of examples in which lncRNAs are responsive to hyperglycemia and clearly involved in regulation of genes and pathways associated with the development of diabetic complications.Critical Issues: As there are likely thousands of lncRNAs that are expressed in any given tissue, understanding how they are regulated and function in the normal healthy state as well as pathological states is a challenge.Future Directions: Further studies in how lncRNAs are involved in the development and progression of diabetic complications as well as development of methods to target dysregulated lncRNAs or evaluate them as biomarkers of early detection of organ dysfunction will be highly beneficial to treating diabetic patients.
  • 10.

    【2hr】Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma

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    机译 NADPH驱动β-拉帕酮在头颈部鳞状细胞癌中的基因组规模建模。
    摘要：Aims: The purpose of this study was to investigate differential nicotinamide adenine dinucleotide phosphate, reduced (NADPH) production between radiation-sensitive and -resistant head and neck squamous cell carcinoma (HNSCC) cell lines and whether these differences are predictive of sensitivity to the chemotherapeutic β-lapachone.Results: We have developed a novel human genome-scale metabolic modeling platform that combines transcriptomic, kinetic, thermodynamic, and metabolite concentration data. Upon incorporation of this information into cell line-specific models, we observed that the radiation-resistant HNSCC model redistributed flux through several major NADPH-producing reactions. Upon RNA interference of canonical NADPH-producing genes, the metabolic network can further reroute flux through alternate NADPH biosynthesis pathways in a cell line-specific manner. Model predictions of perturbations in cellular NADPH production after gene knockdown match well with experimentally verified effects of β-lapachone treatment on NADPH/NADP+ ratio and cell viability. This computational approach accurately predicts HNSCC-specific oxidoreductase genes that differentially affect cell viability between radiation-responsive and radiation-resistant cancer cells upon β-lapachone treatment.Innovation: Quantitative genome-scale metabolic models that incorporate multiple levels of biological data are applied to provide accurate predictions of responses to a NADPH-dependent redox cycling chemotherapeutic drug under a variety of perturbations.Conclusion: Our modeling approach suggests differences in metabolism and β-lapachone redox cycling that underlie phenotypic differences in radiation-sensitive and -resistant cancer cells. This approach can be extended to investigate the synergistic action of NAD(P)H: quinone oxidoreductase 1 bioactivatable drugs and radiation therapy. Antioxid. Redox Signal. 29, 937–952.
  • 11.

    【2hr】Systems Biology Approaches to Redox Metabolism in Stress and Disease States

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    机译 应激和疾病状态下氧化还原代谢的系统生物学方法
    摘要：Significance: All cellular metabolic processes are tied to the cellular redox environment. Therefore, maintaining redox homeostasis is critically important for normal cell function. Indeed, redox stress contributes to the pathobiology of many human diseases. The cellular redox response system is composed of numerous interconnected components, including free radicals, redox couples, protein thiols, enzymes, metabolites, and transcription factors. Moreover, interactions between and among these factors are regulated in time and space. Owing to their complexity, systems biology approaches to the characterization of the cellular redox response system may provide insights into novel homeostatic mechanisms and methods of therapeutic reprogramming.Recent Advances: The emergence and development of systems biology has brought forth a set of innovative technologies that provide new avenues for studying redox metabolism. This article will review these systems biology approaches and their potential application to the study of redox metabolism in stress and disease states.Critical Issues: Clarifying the scope of biological intermediaries affected by dysregulated redox metabolism requires methods that are suitable for analyzing big datasets as classical methods that do not account for multiple interactions are unlikely to portray the totality of perturbed metabolic systems.Future Directions: Given the diverse redox microenvironments within cells, it will be important to improve the spatial resolution of omic approaches. Futures studies on the integration of multiple systems-based methods and heterogeneous omics data for redox metabolism are required to accelerate the development of the field of redox systems biology. Antioxid. Redox Signal. 29, 953–972.
  • 12.

    【2hr】Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer

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    机译 氧化还原悖论：一种新的方法来治疗抗药性癌症
    摘要：Significance: Cancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers.Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies.Critical Issues: The major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H2O2) as the driver molecule for cancer progression as well as a target for cancer treatment.Future Directions: Based on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment.
  • 13.

    【2hr】“Only a Life Lived for Others Is Worth Living”: Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions

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    机译 “只有为他人而活的生命才是值得的生命”：细胞命运决策中含氧磷脂的氧化还原信号传递
    摘要：Significance: Oxygenated polyunsaturated lipids are known to play multi-functional roles as essential signals coordinating metabolism and physiology. Among them are well-studied eicosanoids and docosanoids that are generated via phospholipase A2 hydrolysis of membrane phospholipids and subsequent oxygenation of free polyunsaturated fatty acids (PUFA) by cyclooxygenases and lipoxygenases.Recent Advances: There is an emerging understanding that oxygenated PUFA-phospholipids also represent a rich signaling language with yet-to-be-deciphered details of the execution machinery—oxygenating enzymes, regulators, and receptors. Both free and esterified oxygenated PUFA signals are generated in cells, and their cross-talk and inter-conversion through the de-acylation/re-acylation reactions is not sufficiently explored.Critical Issues: Here, we review recent data related to oxygenated phospholipids as important damage signals that trigger programmed cell death pathways to eliminate irreparably injured cells and preserve the health of multicellular environments. We discuss the mechanisms underlying the trans-membrane redistribution and generation of oxygenated cardiolipins in mitochondria by cytochrome c as pro-apoptotic signals. We also consider the role of oxygenated phosphatidylethanolamines as proximate pro-ferroptotic signals.Future Directions: We highlight the importance of sequential processes of phospholipid oxygenation and signaling in disease contexts as opportunities to use their regulatory mechanisms for the identification of new therapeutic targets.
  • 14.

    【2hr】Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate

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    机译 辐射介导的肿瘤生长抑制作用与抗坏血酸循环的氧化还原活性化合物显着增强。
    摘要：Aims: We aim here to demonstrate that radiation (RT) enhances tumor sensitization by only those Mn complexes that are redox active and cycle with ascorbate (Asc), thereby producing H2O2 and utilizing it subsequently in protein S-glutathionylation in a glutathione peroxidase (GPx)-like manner. In turn, such compounds affect cellular redox environment, described by glutathione disulfide (GSSG)/glutathione (GSH) ratio, and tumor growth. To achieve our goal, we tested several Mn complexes of different chemical and physical properties in cellular and animal flank models of 4T1 breast cancer cell. Four other cancer cell lines were used to substantiate key findings.Results: Joint administration of cationic Mn porphyrin (MnP)-based redox active compounds, MnTE-2-PyP5+ or MnTnBuOE-2-PyP5+ with RT and Asc contributes to high H2O2 production in cancer cells and tumor, which along with high MnP accumulation in cancer cells and tumor induces the largest suppression of cell viability and tumor growth, while increasing GSSG/GSH ratio and levels of total S-glutathionylated proteins. Redox-inert MnP, MnTBAP3− and two other different types of redox-active Mn complexes (EUK-8 and M40403) were neither efficacious in the cellular nor in the animal model. Such outcome is in accordance with their inability to catalyze Asc oxidation and mimic GPx.Innovation: We provided here the first evidence how structure-activity relationship between the catalytic potency and the redox properties of Mn complexes controls their ability to impact cellular redox environment and thus enhance the radiation and ascorbate-mediated tumor suppression.Conclusions: The interplay between the accumulation of cationic MnPs and their potency as catalysts for oxidation of Asc, protein cysteines, and GSH controls the magnitude of their anticancer therapeutic effects.
  • 15.

    【2hr】Oxidative Stress in Mesenchymal Stem Cell Senescence: Regulation by Coding and Noncoding RNAs

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    机译 间充质干细胞衰老中的氧化应激：编码和非编码RNA的调节。
    摘要：Significance: Mesenchymal stem cells (MSCs), adult stem cells with the potential of differentiation into mesodermal lineages, play an important role in tissue homeostasis and regeneration. In different organs, a subpopulation of MSCs is located near the vasculature and possibly represents the original source of lineage-committed mesenchymal progenitors.Recent Advances: The plasticity and immune characteristics of MSCs render them a preferential tool for regenerative cell therapy.Critical Issues: The culture expansion needed before MSC transplantation is associated with cellular senescence. Moreover, accelerated senescence of the total and perivascular MSC pool has been observed in humans and mouse models of premature aging disorders. MSC dysfunction is acknowledged as a culprit for the aging-associated degeneration of mesodermal tissues, but the underlying epigenetic pathways remain elusive. This article reviews current understanding of mechanisms impinging on MSC health, including oxidative stress, Nrf2-antioxidant responsive element activity, sirtuins, noncoding RNAs, and PKCs.Future Directions: We provide evidence that epigenetic profiling of MSCs is utilitarian to the prediction of therapeutic outcomes. In addition, strategies that target oxidative stress-associated mechanisms represent promising approaches to counteract the detrimental effect of age and senescence in MSCs.—Antioxid. Redox Signal. 29, 864–879.
  • 16.

    【2hr】Short and Long Noncoding RNAs Regulate the Epigenetic Status of Cells

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    机译 短和长的非编码RNA调节细胞的表观遗传状态。
    摘要：Significance: The concepts of junk DNA and transcriptional noise are long gone as the existence of noncoding RNAs (ncRNAs) has been tested extensively in recent years. Given that the epigenetic status of cells affects many biological processes, how ncRNAs mechanistically contribute to these processes is of great interest.Recent Advances: Recent studies show that various ncRNAs interact with epigenetic and/or transcription factors to modulate the epigenetic status of cells directly and/or indirectly. There exists growing interest in the field of cardiovascular research to understand the roles of ncRNAs. Due to the large number of ncRNAs in the mammalian genome, only a handful of ncRNAs have been functionally elucidated, which makes it difficult to understand how ncRNAs interact with protein-coding genes and their encoded proteins.Critical Issues: Although the canonical function of microRNAs (miRNAs) to inhibit the translation of protein-coding genes is well established, the number of functionally annotated long noncoding RNAs (lncRNAs) is still small, which is especially true in the heart.Future Directions: Future studies must connect the epigenetic controls of various cellular phenomena by incorporating both miRNAs and lncRNAs. Antioxid. Redox Signal. 29, 832–845.
  • 17.

    【2hr】Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease

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    机译 阿尔茨海默氏病细胞内钙信号传导异常
    摘要：Significance: Calcium (Ca2+) hypothesis of Alzheimer's disease (AD) gains popularity. It points to new signaling pathways that may underlie AD pathogenesis. Based on calcium hypothesis, novel targets for the development of potential AD therapies are identified.Recent Advances: Recently, the key role of neuronal store-operated calcium entry (nSOCE) in the development of AD has been described. Correct regulation of nSOCE is necessary for the stability of postsynaptic contacts to preserve the memory formation. Molecular identity of hippocampal nSOCE is defined. Perspective nSOCE-activating molecule, prototype of future anti-AD drugs, is described.Critical Issues: Endoplasmic reticulum Ca2+ overload happens in many but not in all AD models. The nSOCE targeting therapy described in this review may not be universally applicable.Future Directions: There is a need to determine whether AD is a syndrome with one critical signaling pathway that initiates pathology, or it is a disorder with many different signaling pathways that are disrupted simultaneously or one after each other. It is necessary to validate applicability of nSOCE-activating therapy for the development of anti-AD medication. There is an experimental correlation between downregulated nSOCE and disrupted postsynaptic contacts in AD mouse models. Signaling mechanisms downstream of nSOCE which are responsible for the regulation of stability of postsynaptic contacts have to be discovered. That will bring new targets for the development of AD-preventing therapies. Antioxid. Redox Signal. 29, 1176–1188.
  • 18.

    【2hr】Is Magnetic Resonance Imaging Detection of Kidney Iron Deposition Increased in Haptoglobin 2-2 Genotype Carriers with Type 1 Diabetes?

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    机译 在患有1型糖尿病的结合珠蛋白2-2基因型携带者中，磁共振成像检测肾脏铁沉积是否增加？
    摘要：Haptoglobin's (Hp) main role is to bind free hemoglobin (Hb), reducing its oxidative potential. The Hp–Hb complex formed is cleared from the circulation by macrophage receptor CD163. In diabetes, impaired Hp 2-2–Hb CD163 clearance and abnormal glomerular permeability allow the large Hp 2-2–Hb complex to cross the barrier, where its redox active iron leads to cellular toxicity. Although Hp 2-2 predicts renal function decline, whether renal iron deposition differs by Hp is unknown. We used renal quantitative T2* magnetic resonance imaging to estimate iron level in the cortex and medullar of type 1 diabetes (T1D) adults [15 Hp 1-1 and 15 Hp 2-2 carriers of similar age (53 years), duration (45 years), and gender]. Total kidney iron level was estimated as the sum of the cortex and medullar iron. Albuminuria was defined as urinary albumin to creatinine ratio >30 mg/g in two of three samples. Total kidney iron did not differ by gender or Hp but was higher in those with albuminuria (p = 0.05), an association confined to Hp 2-2 carriers (p = 0.04 vs. p = 0.51 in Hp 1-1). These data lead to the hypothesis that kidney iron deposition is increased among Hp 2-2 carriers with albuminuria in T1D. Antioxid. Redox Signal. 29, 735–741.
  • 19.

    【2hr】Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling

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    机译 线粒体解偶联蛋白：细胞氧化还原信号的微调。
    摘要：Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling.Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells.Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling.Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714.
  • 20.

    【2hr】Redox-Sensing Under Hypochlorite Stress and Infection Conditions by the Rrf2-Family Repressor HypR in Staphylococcus aureus

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    机译 金黄色葡萄球菌Rrf2家族阻遏物HypR在次氯酸盐胁迫和感染条件下对氧化还原的感知。
    摘要：Aims: Staphylococcus aureus is a major human pathogen and has to cope with reactive oxygen and chlorine species (ROS, RCS) during infections, which requires efficient protection mechanisms to avoid destruction. Here, we have investigated the changes in the RNA-seq transcriptome by the strong oxidant sodium hypochlorite (NaOCl) in S. aureus USA300 to identify novel redox-sensing mechanisms that provide protection under infection conditions.Results: NaOCl stress caused an oxidative stress response in S. aureus as indicated by the induction of the PerR, QsrR, HrcA, and SigmaB regulons in the RNA-seq transcriptome. The hypR-merA (USA300HOU_0588-87) operon was most strongly upregulated under NaOCl stress, which encodes for the Rrf2-family regulator HypR and the pyridine nucleotide disulfide reductase MerA. We have characterized HypR as a novel redox-sensitive repressor that controls MerA expression and directly senses and responds to NaOCl and diamide stress via a thiol-based mechanism in S. aureus. Mutational analysis identified Cys33 and the conserved Cys99 as essential for NaOCl sensing, while Cys99 is also important for repressor activity of HypR in vivo. The redox-sensing mechanism of HypR involves Cys33-Cys99 intersubunit disulfide formation by NaOCl stress both in vitro and in vivo. Moreover, the HypR-controlled flavin disulfide reductase MerA was shown to protect S. aureus against NaOCl stress and increased survival in J774A.1 macrophage infection assays.Conclusion and Innovation: Here, we identified a new member of the widespread Rrf2 family as redox sensor of NaOCl stress in S. aureus that uses a thiol/disulfide switch to regulate defense mechanisms against the oxidative burst under infections in S. aureus. Antioxid. Redox Signal. 29, 615–636.
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