Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells.

PubMed

Guidi, Novella; Sacma, Mehmet; Ständker, Ludger; Soller, Karin; Marka, Gina; Eiwen, Karina; Weiss, Johannes M; Kirchhoff, Frank; Weil, Tanja; Cancelas, Jose A; Florian, Maria Carolina; Geiger, Hartmut

2017-04-03

Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age-related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long-term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin-cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma-derived OPN for HSC aging and identify thrombin-cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging. © 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors.

PubMed

Henry, Curtis J; Casás-Selves, Matias; Kim, Jihye; Zaberezhnyy, Vadym; Aghili, Leila; Daniel, Ashley E; Jimenez, Linda; Azam, Tania; McNamee, Eoin N; Clambey, Eric T; Klawitter, Jelena; Serkova, Natalie J; Tan, Aik Choon; Dinarello, Charles A; DeGregori, James

2015-12-01

The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRAS(V12), or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of α-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRAS(V12)-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation--a common feature of aging--has the potential to limit aging-associated oncogenesis.

The Plasma Proteome Is Associated with Anthropometric Status of Undernourished Nepalese School-Aged Children.

PubMed

Lee, Sun Eun; Stewart, Christine P; Schulze, Kerry J; Cole, Robert N; Wu, Lee S-F; Yager, James D; Groopman, John D; Khatry, Subarna K; Adhikari, Ramesh Kant; Christian, Parul; West, Keith P

2017-03-01

Background: Malnutrition affects body growth, size, and composition of children. Yet, few functional biomarkers are known to be associated with childhood morphology. Objective: This cross-sectional study examined associations of anthropometric indicators of height, musculature, and fat mass with plasma proteins by using proteomics in a population cohort of school-aged Nepalese children. Methods: Height, weight, midupper arm circumference (MUAC), triceps and subscapular skinfolds, upper arm muscle area (AMA), and arm fat area (AFA) were assessed in 500 children 6-8 y of age. Height-for-age z scores (HAZs), weight-for-age z scores (WAZs), and body mass index-for-age z scores (BAZs) were derived from the WHO growth reference. Relative protein abundance was quantified by using tandem mass spectrometry. Protein-anthropometry associations were evaluated by linear mixed-effects models and identified as having a false discovery rate ( q ) <5%. Results: Among 982 proteins, 1, 10, 14, and 17 proteins were associated with BAZ, HAZ, MUAC, and AMA, respectively ( q < 0.05). Insulin-like growth factor (IGF)-I, 2 IGF-binding proteins, and carnosinase-1 were associated with both HAZ and AMA. Proteins involved in nutrient transport, activation of innate immunity, and bone mineralization were associated with HAZ. Several extracellular matrix proteins were positively associated with AMA alone. The proteomes of MUAC and AMA substantially overlapped, whereas no proteins were associated with AFA or triceps and subscapular skinfolds. Myosin light-chain kinase, possibly reflecting leakage from muscle, was inversely associated with BAZ. The proteome of WAZ was the largest ( n = 33) and most comprehensive, including proteins involved in neural development and oxidative stress response, among others. Conclusions: Plasma proteomics confirmed known biomarkers of childhood growth and revealed novel proteins associated with lean mass in chronically undernourished children. Identified proteins

Aging-associated shifts in functional status of mast cells located by adult and aged mesenteric lymphatic vessels

PubMed Central

Chatterjee, Victor

2012-01-01

We had previously proposed the presence of permanent stimulatory influences in the tissue microenvironment surrounding the aged mesenteric lymphatic vessels (MLV), which influence aged lymphatic function. In this study, we performed immunohistochemical labeling of proteins known to be present in mast cells (mast cell tryptase, c-kit, prostaglandin D2 synthase, histidine decarboxylase, histamine, transmembrane protein 16A, and TNF-α) with double verification of mast cells in the same segment of rat mesentery containing MLV by labeling with Alexa Fluor 488-conjugated avidin followed by toluidine blue staining. Additionally, we evaluated the aging-associated changes in the number of mast cells located by MLV and in their functional status by inducing mast cell activation by various activators (substance P; anti-rat DNP Immunoglobulin E; peptidoglycan from Staphyloccus aureus and compound 48/80) in the presence of ruthenium red followed by subsequent staining by toluidine blue. We found that there was a 27% aging-associated increase in the total number of mast cells, with an ∼400% increase in the number of activated mast cells in aged mesenteric tissue in resting conditions with diminished ability of mast cells to be newly activated in the presence of inflammatory or chemical stimuli. We conclude that higher degree of preactivation of mast cells in aged mesenteric tissue is important for development of aging-associated impairment of function of mesenteric lymphatic vessels. The limited number of intact aged mast cells located close to the mesenteric lymphatic compartments to react to the presence of acute stimuli may be considered contributory to the aging-associated deteriorations in immune response. PMID:22796537

Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A

PubMed Central

Vallejo, Abbe N.; Michel, Joshua J.; Bale, Laurie K.; Lemster, Bonnie H.; Borghesi, Lisa; Conover, Cheryl A.

2009-01-01

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA−/− mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy, 18-month-old PAPPA−/− mice maintain discrete thymic cortex and medulla densely populated by CD4+CD8+ thymocytes that are capable of differentiating into single-positive CD4 and CD8 T cells. Old PAPPA−/− mice have high levels of T cell receptor excision circles, and have bone marrows enriched for subsets of thymus-seeding progenitors. PAPPA−/− mice have an overall larger pool of naive T cells, and also exhibit an age-dependent accumulation of CD44+CD43+ memory T cells similar to wild-type mice. However, CD43+ T cell subsets of old PAPPA−/− mice have significantly lower prevalence of 1B11 and S7, glycosylation isoforms known to inhibit T cell activation with normal aging. In bioassays of cell activation, splenic T cells of old PAPPA−/− mice have high levels of activation antigens and cytokine production, and also elicit Ig production by autologous B cells at levels equivalent to young wild-type mice. These data suggest an IGF-immune axis of healthy longevity. Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune homeostasis during postnatal development and aging. PMID:19549878

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection

PubMed Central

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh–B cell interactions. PMID:29109730

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection.

PubMed

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh-B cell interactions.

Plasma TNF-α Is Associated with Inflammation and Nutrition Status in Community-Dwelling Japanese Elderly.

PubMed

Oe, Yukiko; Mochizuki, Kazuki; Miyauchi, Rie; Misaki, Yasumi; Kasezawa, Nobuhiko; Tohyama, Kazushige; Goda, Toshinao

2015-01-01

Inflammation has been suggested to play an important role in age-related chronic diseases and disability, and it is associated with nutritional status including obesity and malnutrition. While numerous studies have examined the validity of inflammatory markers in the population studies in Caucasian elderly people, very little information is available for the factors affecting inflammatory markers in Asian elderly people. Among inflammatory markers frequently used for the studies of aging, tumor necrosis factor α (TNF-α) is produced mainly by macrophages, and contributes to production of interleukin-6 (IL-6) and C-reactive protein (CRP), thus directing a chronic inflammatory process in the body. In the present study, we examined the associations between plasma TNF-α level and several factors related to nutrition status, including BMI, albumin, and energy intake in community-dwelling Japanese elderly. We conducted a cross-sectional study of 390 men and women aged 70-86 y (average 73.5 y), who participated in health check-ups. Associations between plasma TNF-α levels, other clinical parameters, and lifestyle factors were analyzed using Spearman's rank correlation coefficient analysis and multiple linear regression analysis. In elderly men, plasma TNF-α level was positively associated with age, white blood cell count, monocyte count, plasma CRP level, serum creatinine, ureic acid, and triacylglycerol levels, and negatively associated with albumin/globulin ratio, eGFR, and serum HDL-cholesterol level. In elderly women, plasma TNF-α level was positively associated with age, plasma CRP level, and serum triacylglycerol level, and negatively associated with serum albumin and HDL-cholesterol levels. The results of this study suggest that plasma TNF-α is associated with inflammation and insulin resistance in both Japanese elderly men and women, and a prominent association of TNF-α with malnutrition status was observed in elderly women.

Protein diffusion in plant cell plasma membranes: the cell-wall corral.

PubMed

Martinière, Alexandre; Runions, John

2013-01-01

Studying protein diffusion informs us about how proteins interact with their environment. Work on protein diffusion over the last several decades has illustrated the complex nature of biological lipid bilayers. The plasma membrane contains an array of membrane-spanning proteins or proteins with peripheral membrane associations. Maintenance of plasma membrane microstructure can be via physical features that provide intrinsic ordering such as lipid microdomains, or from membrane-associated structures such as the cytoskeleton. Recent evidence indicates, that in the case of plant cells, the cell wall seems to be a major player in maintaining plasma membrane microstructure. This interconnection / interaction between cell-wall and plasma membrane proteins most likely plays an important role in signal transduction, cell growth, and cell physiological responses to the environment.

Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells.

PubMed

Zhang, Yan; Schuetz, John D; Elmquist, William F; Miller, Donald W

2004-11-01

Several multidrug resistance-associated protein (MRP) homologs are expressed in brain microvessel endothelial cells forming the blood-brain barrier (BBB). The influence of these MRP transporters on BBB permeability will be dependent on their localization within the brain microvessel endothelial cells. Using two different and complementary approaches, the localization of various MPR homologs (MRP1, MRP4, and MRP5) was examined in primary cultured bovine brain microvessel endothelial cells (BBMECs). The first approach involved centrifugal separation of apical and basolateral plasma membranes of cultured BBMECs. The membrane fractions were then subjected to Western blot analysis for MRPs. The second approach used confocal laser scanning microscopy to determine membrane localization of MRPs in BBMECs. Results show a predominantly apical plasma membrane distribution for MRP1 and MRP5, and an almost equal distribution of MRP4 on the apical and basolateral plasma membrane of BBMECs. These studies provide the first demonstration of the localization of MRP1, MRP4, and MRP5 homologs in brain microvessel endothelial cells. The present studies also indicate that the localization of MRPs in the endothelial cells forming the BBB is different from that observed in polarized epithelial cells and thus may contribute to the reduced entry and enhanced elimination of organic anions and nucleotides in the brain.

Association of anthropometric characteristics with the risk of malignant lymphoma and plasma cell myeloma in a Japanese population: a population-based cohort study.

PubMed

Kanda, Junya; Matsuo, Keitaro; Inoue, Manami; Iwasaki, Motoki; Sawada, Norie; Shimazu, Taichi; Yamaji, Taiki; Sasazuki, Shizuka; Tsugane, Shoichiro

2010-06-01

Although Asian and Western populations differ markedly in anthropometric characteristics and the incidence of malignant lymphoma and plasma cell myeloma, few studies have evaluated the associations between these variables among Asian populations. We conducted a large-scale, population-based prospective study in a Japanese cohort that included 45,007 men and 49,540 women ages 40 to 69 years at baseline. During an average follow-up period of 13 years, 257 cases of malignant lymphoma and 88 of plasma cell myeloma were identified. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated with the use of a Cox regression model adjusted for potential confounders. Compared with the 1st quartile, categorization in the 4th quartile for height showed a positive association with lymphoid neoplasm risk (HR, 1.38; 95% CI, 1.00-1.91), and the association was significant among men (HR, 1.72; 95% CI, 1.11-2.66). A similar trend was observed for subcategories of malignant lymphoma, plasma cell myeloma, and non-Hodgkin lymphoma, albeit the associations were weak due to the small number of subjects in each category. In contrast, weight and body mass index were not associated with risk of lymphoid neoplasm. Height was positively associated with risk of lymphoid neoplasm in a Japanese population. Our data suggested that early life exposure to growth-related hormones, such as insulin-like growth factors and growth hormones, or genetic factors relating to height may affect the risk of lymphoid neoplasm. Copyright 2010 AACR.

Plasma Amyloid Is Associated with White Matter and Subcortical Alterations and Is Modulated by Age and Seasonal Rhythms in Mouse Lemur Primates.

PubMed

Gary, Charlotte; Hérard, Anne-Sophie; Hanss, Zoé; Dhenain, Marc

2018-01-01

Accumulation of amyloid-β (Aβ) peptides in the brain is a critical early event in the pathogenesis of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. There is increasing interest in measuring levels of plasma Aβ since this could help in diagnosis of brain pathology. However, the value of plasma Aβ in such a diagnosis is still controversial and factors modulating its levels are still poorly understood. The mouse lemur ( Microcebus murinus ) is a primate model of cerebral aging which can also present with amyloid plaques and whose Aβ is highly homologous to humans'. In an attempt to characterize this primate model and to evaluate the potential of plasma Aβ as a biomarker for brain alterations, we measured plasma Aβ 40 concentration in 21 animals aged from 5 to 9.5 years. We observed an age-related increase in plasma Aβ 40 levels. We then evaluated the relationships between plasma Aβ 40 levels and cerebral atrophy in these mouse lemurs. Voxel-based analysis of cerebral MR images (adjusted for the age/sex/brain size of the animals), showed that low Aβ 40 levels are associated with atrophy of several white matter and subcortical brain regions. These results suggest that low Aβ 40 levels in middle-aged/old animals are associated with brain deterioration. One special feature of mouse lemurs is that their metabolic and physiological parameters follow seasonal changes strictly controlled by illumination. We evaluated seasonal-related variations of plasma Aβ 40 levels and found a strong effect, with higher plasma Aβ 40 concentrations in winter conditions compared to summer. This question of seasonal modulation of Aβ plasma levels should be addressed in clinical studies. We also focused on the amplitude of the difference between plasma Aβ 40 levels during the two seasons and found that this amplitude increases with age. Possible mechanisms leading to these seasonal changes are discussed.

Distinct AGO1 and AGO2 associated miRNA profiles in human cells and blood plasma

PubMed Central

Turchinovich, Andrey; Burwinkel, Barbara

2012-01-01

Studies of miRNA association with Argonaute (AGO) proteins in mammalian cells have indicated lack of bias toward particular AGO. However, to our knowledge, the use of quantitative methods for studying miRNA association with different AGOs has not been reported so far. In this work we compared the total miRNA content in AGO1 and AGO2 immunoprecipitates obtained from MCF7 adenocarcinoma cells using TaqMan Low Density miRNA Arrays and successfully verified selected miRNAs with qPCR. For most of the miRNA species AGO1 and AGO2 profiles were well correlated, however, some miRNAs demonstrated consistent biases toward one of the Argonautes. Furthermore, miRNAs which were predominantly AGO2-associated derived mostly from sense strands of the corresponding pre-miRNAs while the majority of AGO1 biased miRNAs originated from antisense strands of the pre-miRNAs. Additionally, we show that circulating miRNA in human blood plasma can be immunoprecipitated with both AGO1 and AGO2 antibody. However, unlike in cell lysates, AGO1 and AGO2 associated miRNA profiles in plasma did not correlate, indicating that many cell types contribute to circulating miRNA (given that expression of AGO proteins is tissue specific). Furthermore, AGO-specific miRNA profiles in blood cells differed significantly from miRNAs profiles in plasma indicating that most circulating miRNAs are likely to derive from non-blood cells. Since circulating miRNAs hold great promise as biomarkers for numerous cancers and other diseases, we hypothesize that AGO-specific miRNA profiles might add an additional dimension to circulating miRNA-based diagnostics. PMID:22858679

Correlation and association between plasma platelet-, monocyte- and endothelial cell-derived microparticles in hypertensive patients with type 2 diabetes mellitus.

PubMed

Nomura, Shosaku; Inami, Norihito; Shouzu, Akira; Urase, Fumiaki; Maeda, Yasuhiro

2009-09-01

Elevated platelet-derived mircoparticles (MP) (PDMP), endothelial cell-derived MP (EDMP), and monocyte-derived MP (MDMP) concentrations are documented in almost all thrombotic diseases. However, the intricate interactions between PDMP, MDMP and EDMP in hypertensive patients with or without type 2 diabetes remains poorly understood. Therefore, to clarify the correlation and association of MPs, we measured and analysed the levels of MPs in 359 hypertensive patients. We compared the results of chemokines, cell adhesion molecules, platelet activation markers and microparticles in hypertensive patients with and without type 2 diabetes mellitus. The levels of all markers were significantly higher in the hypertensive patients with diabetes than in the non-diabetic patients. For hypertensive patients with diabetes, univariate analysis showed that age, body mass index, systolic blood pressure, high density lipoprotein cholesterol (HDL-CHO), creatinine (CRTN), soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble CD40 ligand (sCD40L), regulated on activation normally T-cell expressed and secreted (RANTES), monocyte chemotactic peptide-1 (MCP-1), MDMP and EDMP were significantly associated with PDMP. In addition, systolic blood pressure, HDL cholesterol, sP-selectin, sE-selectin, sVCAM-1, sCD40L, RANTES, MDMP and EDMP were significant factors in the multivariate model with PDMP. Furthermore, a correlation between plasma PDMP and MDMP or EDMP in hypertensive patients were observed both with and without diabetes. These results suggest that the existence of diabetes mellitus affects PDMP generation in hypertensive patients and that enhanced plasma levels of PDMP and an association between the plasma levels of PDMP, MDMP and EDMP may result in the development of atherothrombotic complications in hypertensive patients.

Plasma membrane-associated platforms: dynamic scaffolds that organize membrane-associated events.

PubMed

Astro, Veronica; de Curtis, Ivan

2015-03-10

Specialized regions of the plasma membrane dedicated to diverse cellular processes, such as vesicle exocytosis, extracellular matrix remodeling, and cell migration, share a few cytosolic scaffold proteins that associate to form large plasma membrane-associated platforms (PMAPs). PMAPs organize signaling events and trafficking of membranes and molecules at specific membrane domains. On the basis of the intrinsic disorder of the proteins constituting the core of these PMAPs and of the dynamics of these structures at the periphery of motile cells, we propose a working model for the assembly and turnover of these platforms. Copyright © 2015, American Association for the Advancement of Science.

CPT1A methylation is associated with plasma adiponectin.

PubMed

Aslibekyan, S; Do, A N; Xu, H; Li, S; Irvin, M R; Zhi, D; Tiwari, H K; Absher, D M; Shuldiner, A R; Zhang, T; Chen, W; Tanner, K; Hong, C; Mitchell, B D; Berenson, G; Arnett, D K

2017-03-01

Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression coefficient ± SE = 0.01 ± 0.001, P = 3.4 × 10 -13 ) between plasma adiponectin levels and methylation of a CpG site in CPT1A, a key player in fatty acid metabolism. The association was replicated (n = 474, P = 0.0009) in whole blood samples from the Amish participants of the Heredity and Phenotype Intervention (HAPI) Heart Study as well as White (n = 592, P = 0.0005) but not Black (n = 243, P = 0.18) participants of the Bogalusa Heart Study (BHS). The association remained significant upon adjusting for BMI and smoking in GOLDN and HAPI but not BHS. We also identified associations between methylation loci in RNF145 and UFM1 and plasma adiponectin in GOLDN and White BHS participants, although the association was not robust to adjustment for BMI or smoking. We have identified and replicated associations between several biologically plausible loci and plasma adiponectin. These findings support the importance of epigenetic processes in metabolic traits, laying the groundwork for future translational applications. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All

Unusual presentation Of Sjögren-associated neuropathy with plasma cell-rich infiltrate.

PubMed

Naddaf, Elie; Berini, Sarah E; B Dyck, P James; Laughlin, Ruple S

2017-04-01

Sjögren syndrome is thought to be a lymphocyte-driven process. Peripheral nervous system involvement occurs in about 20%-25% of patients. A sensory-predominant, large-fiber peripheral neuropathy is most common, and it is usually associated with a subacute to chronic presentation. We report a rare case of an acute Sjögren-associated, sensory predominant, length-dependent peripheral neuropathy mimicking Guillain-Barré syndrome. The patient presented with sensory ataxia preceded by fever and polyarthralgia. She gave a history of years of dry eyes and dry mouth. She had a positive Shirmer test, abnormal salivary gland scan, and positive SS-A and SS-B antibodies. A sural nerve biopsy showed an unusual, dense, non-IgG4, polyclonal, plasma-cell perivascular infiltrate. The patient responded to treatment with weekly pulse intravenous methylprednisolone. Sjögren syndrome can present with acute-onset, sensory predominant peripheral neuropathy. The role of plasma cells in Sjögren syndrome is unexplored and deserves further study. Muscle Nerve 55: 605-608, 2017. © 2016 Wiley Periodicals, Inc.

Inverse association between plasma homocysteine concentrations and type 2 diabetes mellitus among a middle-aged and elderly Chinese population.

PubMed

Yu, C; Wang, J; Wang, F; Han, X; Hu, H; Yuan, J; Miao, X; Yao, P; Wei, S; Wang, Y; Liang, Y; Chen, W; Zhang, X; Guo, H; Yang, H; Tang, Y; Zheng, D; Wu, T; He, M

2018-03-01

Plasma homocysteine concentrations have been reported to be associated with type 2 diabetes mellitus (T2DM) with controversial findings. The aim of the present study was to investigate the association between plasma homocysteine concentrations and T2DM. A cross-sectional study including 19,085 eligible participants derived from the Dongfeng-Tongji cohort was conducted. Plasma homocysteine concentrations were measured by Abbott Architect i2000 Automatic analyzer and T2DM was defined according to American Diabetes Association criteria. Logistic regression model was used to explore the association between plasma homocysteine concentrations and T2DM. The prevalence of T2DM was 19.0% in the whole population (mean age 62.9 years), 21.8% in males, and 17.1% in females. In the multivariable logistic regression analyses, compared with those in the lowest quintile, the OR (95% CI) of T2DM was 1.05 (0.92-1.21), 0.99 (0.86-1.14), 0.90 (0.78-1.05), and 0.77 (0.66-0.90) for quintile 2 to quintile 5 of homocysteine concentrations after adjustment for potential confounders (P for trend < 0.0001). Homocysteine concentrations were associated with decreased T2DM prevalence risk (OR = 0.88 per SD increase of homocysteine concentration; 95% CI: 0.84-0.93). A significant interaction between homocysteine concentrations and drinking status on T2DM prevalence risk was observed (P for interaction = 0.03). The inverse association of plasma homocysteine concentrations with T2DM prevalence risk was observed in non-drinkers but not in current drinkers. Plasma homocysteine concentrations were inversely correlated with T2DM among a middle-aged and elderly Chinese population. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

PubMed Central

Gonsalves, Wilson I.; Hitosugi, Taro; Ghosh, Toshi; Jevremovic, Dragan; Petterson, Xuan-Mai; Wellik, Linda; Kumar, Shaji K.; Nair, K. Sreekumaran

2018-01-01

The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13C stable isotope resolved metabolomics (SIRM) using U[13C6]Glucose and U[13C5]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle. Furthermore, the 13C SIRM studies in HMCLs also demonstrate that glutamine is preferentially utilized by the TCA cycle compared with glucose. Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM. Thus, measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM patients offers potential early identification of those patients at high risk of progression to MM, who could benefit from early therapeutic intervention. PMID:29321378

Identification of vinculin as a potential plasma marker for age-related macular degeneration.

PubMed

Kim, Hye-Jung; Woo, Se Joon; Suh, Eui Jin; Ahn, Jeeyun; Park, Ji Hyun; Hong, Hye Kyoung; Lee, Ji Eun; Ahn, Seong Joon; Hwang, Duck Jin; Kim, Ki Woong; Park, Kyu Hyung; Lee, Cheolju

2014-10-08

To identify plasma protein biomarkers for age-related macular degeneration (AMD) using a large-scale quantitative proteomic discovery procedure. Plasma proteomes from 20 exudative AMD patients and 20 healthy control patients were comparatively profiled by four-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteins existing at statistically different levels were validated by enzyme-linked immunosorbent assay (ELISA) and Western blotting in 233 case-controlled samples. Newly discovered plasma biomarkers were further confirmed using in vivo and in vitro experiments. Out of 320 proteins identified, vinculin, protein S100A9, triosephosphate isomerase, protein S100A8, protein Z-dependent protease inhibitor, C-X-C motif chemokine 7, and tenascin X showed significantly differential expression in AMD patient plasma compared to control plasma. Among these, the area under the curve (AUC) for vinculin was 0.871 for discriminating between exudative AMD and controls (n = 201) and 0.879 for discriminating between AMD and controls (n = 233). A proteogenomic combination model using vinculin and two known risk genotypes in ARMS2 and CFH genes additionally provided excellent discrimination of AMD from controls (AUC = 0.916). The plasma level of vinculin was not associated with any confounding clinical variables, such as age, smoking, and other comorbidities. Additionally, vinculin was strongly expressed in retinal pigment epithelial cells of human eyes, and its expression was elevated when exposed to oxidative stress in vitro. Vinculin was identified as a potential plasma biomarker for AMD. The early detection of AMD using novel plasma biomarkers with genetic modeling may enable timely treatment and vision preservation in the elderly. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

The promise of human embryonic stem cells in aging-associated diseases

PubMed Central

Yabut, Odessa; Bernstein, Harold S.

2011-01-01

Aging-associated diseases are often caused by progressive loss or dysfunction of cells that ultimately affect the overall function of tissues and organs. Successful treatment of these diseases could benefit from cell-based therapy that would regenerate lost cells or otherwise restore tissue function. Human embryonic stem cells (hESCs) promise to be an important therapeutic candidate in treating aging-associated diseases due to their unique capacity for self-renewal and pluripotency. To date, there are numerous hESC lines that have been developed and characterized. We will discuss how hESC lines are derived, their molecular and cellular properties, and how their ability to differentiate into all three embryonic germ layers is determined. We will also outline the methods currently employed to direct their differentiation into populations of tissue-specific, functional cells. Finally, we will highlight the general challenges that must be overcome and the strategies being developed to generate highly-purified hESC-derived cell populations that can safely be used for clinical applications. PMID:21566262

Duodenal L cell density correlates with features of metabolic syndrome and plasma metabolites.

PubMed

van Baar, Annieke C G; Prodan, Andrei; Wahlgren, Camilla D; Poulsen, Steen S; Knop, Filip K; Groen, Albert K; Bergman, Jacques J; Nieuwdorp, Max; Levin, Evgeni

2018-05-01

Enteroendocrine cells are essential for the regulation of glucose metabolism, but it is unknown whether they are associated with clinical features of metabolic syndrome (MetS) and fasting plasma metabolites. We aimed to identify fasting plasma metabolites that associate with duodenal L cell, K cell and delta cell densities in subjects with MetS with ranging levels of insulin resistance. In this cross-sectional study, we evaluated L, K and delta cell density in duodenal biopsies from treatment-naïve males with MetS using machine-learning methodology. We identified specific clinical biomarkers and plasma metabolites associated with L cell and delta cell density. L cell density was associated with increased plasma metabolite levels including symmetrical dimethylarginine, 3-aminoisobutyric acid, kynurenine and glycine. In turn, these L cell-linked fasting plasma metabolites correlated with clinical features of MetS. Our results indicate a link between duodenal L cells, plasma metabolites and clinical characteristics of MetS. We conclude that duodenal L cells associate with plasma metabolites that have been implicated in human glucose metabolism homeostasis. Disentangling the causal relation between L cells and these metabolites might help to improve the (small intestinal-driven) pathophysiology behind insulin resistance in human obesity. © 2018 The authors.

Pregnancy and malaria exposure are associated with changes in the B cell pool and in plasma eotaxin levels.

PubMed

Requena, Pilar; Campo, Joseph J; Umbers, Alexandra J; Ome, Maria; Wangnapi, Regina; Barrios, Diana; Robinson, Leanne J; Samol, Paula; Rosanas-Urgell, Anna; Ubillos, Itziar; Mayor, Alfredo; López, Marta; de Lazzari, Elisa; Arévalo-Herrera, Myriam; Fernández-Becerra, Carmen; del Portillo, Hernando; Chitnis, Chetan E; Siba, Peter M; Bardají, Azucena; Mueller, Ivo; Rogerson, Stephen; Menéndez, Clara; Dobaño, Carlota

2014-09-15

Pregnancy triggers immunological changes aimed to tolerate the fetus, but its impact on B lymphocytes is poorly understood. In addition, exposure to the Plasmodium parasite is associated with altered distribution of peripheral memory B cell (MBC) subsets. To study the combined impact of high malaria exposure and pregnancy in B cell subpopulations, we analyzed PBMCs from pregnant and nonpregnant individuals from a malaria-nonendemic country (Spain) and from a high malaria-endemic country (Papua New Guinea). In the malaria-naive cohorts, pregnancy was associated with a significant expansion of all switched (IgD(-)) MBC and a decrease of naive B cells. Malaria-exposed women had more atypical MBC and fewer marginal zone-like MBC, and their levels correlated with both Plasmodium vivax- and Plasmodium falciparum-specific plasma IgG levels. Classical but not atypical MBC were increased in P. falciparum infections. Moreover, active atypical MBC positively correlated with proinflammatory cytokine plasma concentrations and had lower surface IgG levels than the average. Decreased plasma eotaxin (CCL11) levels were associated with pregnancy and malaria exposure and also correlated with B cell subset frequencies. Additionally, active atypical and active classical MBC expressed higher levels of eotaxin receptor CCR3 than the other B cell subsets, suggesting a chemotactic effect of eotaxin on these B cell subsets. These findings are important to understand immunity to infections like malaria that result in negative outcomes for both the mother and the newborn and may have important implications on vaccine development. Copyright © 2014 by The American Association of Immunologists, Inc.

Effect of aging on stem cells

PubMed Central

Ahmed, Abu Shufian Ishtiaq; Sheng, Matilda HC; Wasnik, Samiksha; Baylink, David J; Lau, Kin-Hing William

2017-01-01

Pluripotent stem cells have the remarkable self-renewal ability and are capable of differentiating into multiple diverse cells. There is increasing evidence that the aging process can have adverse effects on stem cells. As stem cells age, their renewal ability deteriorates and their ability to differentiate into the various cell types is altered. Accordingly, it is suggested aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Understanding the role of the aging process in deterioration of stem cell function is crucial, not only in understanding the pathophysiology of aging-associated disorders, but also in future development of novel effective stem cell-based therapies to treat aging-associated diseases. This review article first focuses on the basis of the various aging disease-related stem cell dysfunction. It then addresses the several concepts on the potential mechanism that causes aging-related stem cell dysfunction. It also briefly discusses the current potential therapies under development for aging-associated stem cell defects. PMID:28261550

Plasma membrane associated membranes (PAM) from Jurkat cells contain STIM1 protein is PAM involved in the capacitative calcium entry?

PubMed

Kozieł, Katarzyna; Lebiedzinska, Magdalena; Szabadkai, Gyorgy; Onopiuk, Marta; Brutkowski, Wojciech; Wierzbicka, Katarzyna; Wilczyński, Grzegorz; Pinton, Paolo; Duszyński, Jerzy; Zabłocki, Krzysztof; Wieckowski, Mariusz R

2009-12-01

A proper cooperation between the plasma membrane, the endoplasmic reticulum and the mitochondria seems to be essential for numerous cellular processes involved in Ca(2+) signalling and maintenance of Ca(2+) homeostasis. A presence of microsomal and mitochondrial proteins together with those characteristic for the plasma membrane in the fraction of the plasma membrane associated membranes (PAM) indicates a formation of stabile interactions between these three structures. We isolated the plasma membrane associated membranes from Jurkat cells and found its significant enrichment in the plasma membrane markers including plasma membrane Ca(2+)-ATPase, Na(+), K(+)-ATPase and CD3 as well as sarco/endoplasmic reticulum Ca(2+) ATPase as a marker of the endoplasmic reticulum membranes. In addition, two proteins involved in the store-operated Ca(2+) entry, Orai1 located in the plasma membrane and an endoplasmic reticulum protein STIM1 were found in this fraction. Furthermore, we observed a rearrangement of STIM1-containing protein complexes isolated from Jurkat cells undergoing stimulation by thapsigargin. We suggest that the inter-membrane compartment composed of the plasma membrane and the endoplasmic reticulum, and isolated as a stabile plasma membrane associated membranes fraction, might be involved in the store-operated Ca(2+) entry, and their formation and rebuilding have an important regulatory role in cellular Ca(2+) homeostasis.

Alloimmunization is associated with older age of transfused red blood cells in sickle cell disease.

PubMed

Desai, Payal C; Deal, Allison M; Pfaff, Emily R; Qaqish, Bahjat; Hebden, Leyna M; Park, Yara A; Ataga, Kenneth I

2015-08-01

Red blood cell (RBC) alloimmunization is a significant clinical complication of sickle cell disease (SCD). It can lead to difficulty with cross-matching for future transfusions and may sometimes trigger life-threatening delayed hemolytic transfusion reactions. We conducted a retrospective study to explore the association of clinical complications and age of RBC with alloimmunization in patients with SCD followed at a single institution from 2005 to 2012. One hundred and sixty six patients with a total of 488 RBC transfusions were evaluated. Nineteen patients (11%) developed new alloantibodies following blood transfusions during the period of review. The median age of RBC units was 20 days (interquartile range: 14-27 days). RBC antibody formation was significantly associated with the age of RBC units (P = 0.002), with a hazard ratio of 3.5 (95% CI: 1.71-7.11) for a RBC unit that was 7 days old and 9.8 (95% CI: 2.66-35.97) for a unit that was 35 days old, 28 days after the blood transfusion. No association was observed between RBC alloimmunization and acute vaso-occlusive complications. Although increased echocardiography-derived tricuspid regurgitant jet velocity (TRV) was associated with the presence of RBC alloantibodies (P = 0.02), TRV was not significantly associated with alloimmunization when adjusted for patient age and number of transfused RBC units. Our study suggests that RBC antibody formation is significantly associated with older age of RBCs at the time of transfusion. Prospective studies in patients with SCD are required to confirm this finding. © 2015 Wiley Periodicals, Inc.

Plasma cell leukaemia and other aggressive plasma cell malignancies

PubMed Central

Sher, Taimur; Miller, Kena C.; Deeb, George; Lee, Kelvin; Chanan-Khan, Asher

2014-01-01

Summary Extramedullary plasma cell cancers, such as plasma cell leukemia (PCL) and multiple extramedullary plasmacytomas (MEP) are very aggressive malignancies. These can be primary (de-novo) or secondary due to progressive prior multiple myeloma (MM). Recent reports suggest an increase in incidence of these disorders. Compared to MM, organ invasion is common in PCL, while soft tissue tumors involving the head, neck or paraspinal area are common sites for MEP. Markers of poor prognosis are frequently observed in these extramedullary forms of plasma cell cancers, and survival is significantly inferior compared to patients with MM. Conventional chemotherapeutic and radiotherapy approaches have been employed with variable results. Even high dose chemotherapy with autologous stem cell rescue has not been able to demonstrate consistent improvement in survival outcome. Although not specifically evaluated, novel anti-plasma cell agents, such as the proteasome inhibitor bortezomib, and immunomodulatory drugs, such as lenalidomide, appear to be active against these aggressive cancers. Clinical and translational research directed at improved understanding of disease biology and development of novel therapeutics is urgently needed. PMID:20701603

Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells

PubMed Central

Moorefield, Emily C.; Andres, Sarah F.; Blue, R. Eric; Van Landeghem, Laurianne; Mah, Amanda T.; Santoro, M. Agostina; Ding, Shengli

2017-01-01

Intestinal epithelial stem cells (IESCs) are critical to maintain intestinal epithelial function and homeostasis. We tested the hypothesis that aging promotes IESC dysfunction using old (18-22 months) and young (2-4 month) Sox9-EGFP IESC reporter mice. Different levels of Sox9-EGFP permit analyses of active IESC (Sox9-EGFPLow), activatable reserve IESC and enteroendocrine cells (Sox9-EGFPHigh), Sox9-EGFPSublow progenitors, and Sox9-EGFPNegative differentiated lineages. Crypt-villus morphology, cellular composition and apoptosis were measured by histology. IESC function was assessed by crypt culture, and proliferation by flow cytometry and histology. Main findings were confirmed in Lgr5-EGFP and Lgr5-LacZ mice. Aging-associated gene expression changes were analyzed by Fluidigm mRNA profiling. Crypts culture from old mice yielded fewer and less complex enteroids. Histology revealed increased villus height and Paneth cells per crypt in old mice. Old mice showed increased numbers and hyperproliferation of Sox9-EGFPLow IESC and Sox9-EGFPHigh cells. Cleaved caspase-3 staining demonstrated increased apoptotic cells in crypts and villi of old mice. Gene expression profiling revealed aging-associated changes in mRNAs associated with cell cycle, oxidative stress and apoptosis specifically in IESC. These findings provide new, direct evidence for aging associated IESC dysfunction, and define potential biomarkers and targets for translational studies to assess and maintain IESC function during aging. PMID:28854151

Plasma membrane changes during programmed cell deaths

PubMed Central

Zhang, Yingying; Chen, Xin; Gueydan, Cyril; Han, Jiahuai

2018-01-01

Ruptured and intact plasma membranes are classically considered as hallmarks of necrotic and apoptotic cell death, respectively. As such, apoptosis is usually considered a non-inflammatory process while necrosis triggers inflammation. Recent studies on necroptosis and pyroptosis, two types of programmed necrosis, revealed that plasma membrane rupture is mediated by MLKL channels during necroptosis but depends on non-selective gasdermin D (GSDMD) pores during pyroptosis. Importantly, the morphology of dying cells executed by MLKL channels can be distinguished from that executed by GSDMD pores. Interestingly, it was found recently that secondary necrosis of apoptotic cells, a previously believed non-regulated form of cell lysis that occurs after apoptosis, can be programmed and executed by plasma membrane pore formation like that of pyroptosis. In addition, pyroptosis is associated with pyroptotic bodies, which have some similarities to apoptotic bodies. Therefore, different cell death programs induce distinctive reshuffling processes of the plasma membrane. Given the fact that the nature of released intracellular contents plays a crucial role in dying/dead cell-induced immunogenicity, not only membrane rupture or integrity but also the nature of plasma membrane breakdown would determine the fate of a cell as well as its ability to elicit an immune response. In this review, we will discuss recent advances in the field of apoptosis, necroptosis and pyroptosis, with an emphasis on the mechanisms underlying plasma membrane changes observed on dying cells and their implication in cell death-elicited immunogenicity. PMID:29076500

Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells.

PubMed

Moorefield, Emily C; Andres, Sarah F; Blue, R Eric; Van Landeghem, Laurianne; Mah, Amanda T; Santoro, M Agostina; Ding, Shengli

2017-08-29

Intestinal epithelial stem cells (IESCs) are critical to maintain intestinal epithelial function and homeostasis. We tested the hypothesis that aging promotes IESC dysfunction using old (18-22 months) and young (2-4 month) Sox9-EGFP IESC reporter mice. Different levels of Sox9-EGFP permit analyses of active IESC (Sox9-EGFP Low ), activatable reserve IESC and enteroendocrine cells (Sox9-EGFP High ), Sox9-EGFP Sublow progenitors, and Sox9-EGFP Negative differentiated lineages. Crypt-villus morphology, cellular composition and apoptosis were measured by histology. IESC function was assessed by crypt culture, and proliferation by flow cytometry and histology. Main findings were confirmed in Lgr5-EGFP and Lgr5-LacZ mice. Aging-associated gene expression changes were analyzed by Fluidigm mRNA profiling. Crypts culture from old mice yielded fewer and less complex enteroids. Histology revealed increased villus height and Paneth cells per crypt in old mice. Old mice showed increased numbers and hyperproliferation of Sox9-EGFP Low IESC and Sox9-EGFP High cells. Cleaved caspase-3 staining demonstrated increased apoptotic cells in crypts and villi of old mice. Gene expression profiling revealed aging-associated changes in mRNAs associated with cell cycle, oxidative stress and apoptosis specifically in IESC. These findings provide new, direct evidence for aging associated IESC dysfunction, and define potential biomarkers and targets for translational studies to assess and maintain IESC function during aging.

Renal lesions associated with plasma cell dyscrasias: practical approach to diagnosis, new concepts, and challenges.

PubMed

Herrera, Guillermo A

2009-02-01

Patients with plasma cell dyscrasias (myeloma) may exhibit a variety of renal manifestations as a result of damage from circulating light- and heavy-chain immunoglobulin components produced by the neoplastic plasma cells. The renal alterations can occur in any of the renal compartments, and in a significant number of the cases more than one compartment is affected. Research in the laboratory has helped considerably in providing a solid conceptual understanding of how renal damage occurs. To detail advances that have been made in the diagnosis of these conditions and to provide an account of research accomplishments that have solidified diagnostic criteria. The new knowledge that has been acquired serves to provide a solid platform for the future design of new therapeutic interventions aimed at ameliorating or abolishing the progressive renal damage that typically takes place. Translational efforts have substantially contributed to elucidate mechanistically the molecular events responsible for the renal damage. The spectrum of renal manifestations associated with plasma cell dyscrasias has expanded significantly in the last 10 years. Diagnostic criteria have also been refined. This information has been summarized from work done at several institutions. A number of significant challenges remain in the diagnosis of these conditions, some of which will be discussed in this article. Dealing with these challenges will require additional translational efforts and close cooperation between basic researchers, clinicians, and pathologists in order to improve the diagnostic tools available to renal pathologists and to acquire a more complete understanding of clinical and pathologic manifestations associated with these conditions.

Plasma Pentosidine and Its Association with Mortality in Patients with Chronic Kidney Disease

PubMed Central

Sun, Jia; Qureshi, Abdul Rashid; Isoyama, Naohito; Leurs, Paul; Anderstam, Björn; Heimburger, Olof; Barany, Peter; Stenvinkel, Peter; Lindholm, Bengt

2016-01-01

Background Circulating advanced glycated end-products (AGEs) including pentosidine accumulating in chronic kidney disease (CKD) patients due to retention and increased formation are thought to contribute to cardiovascular disease (CVD). Here we evaluated factors linked to increased plasma pentosidine and its association with mortality in patients with different stages of CKD and undergoing different treatments. Methods Plasma pentosidine, biomarkers of inflammation, oxidative stress and nutritional status were investigated in CKD 1–2 (n = 37), CKD 3–4 (n = 54), CKD 5 non-dialyzed (CKD5-ND; n = 386), peritoneal dialysis (PD; n = 74) and hemodialysis (HD; n = 195) patients. Factors predicting plasma pentosidine were analysed by multivariate regression analysis and mortality risk was assessed by GENMOD procedure. Results Plasma pentosidine levels, which were higher in CKD5-ND, PD and HD groups than in CKD 1–2 group, were significantly lower in PD than in HD patients, and not different between PD patients and CKD5-ND patients. Pentosidine associated inversely with glomerular filtration rate (GFR), and additionally in PD with 8-hydroxy-2‘-deoxyguanosine (8-OHdG), and interleukin 6 (IL-6); in HD with age, IL-6 and body mass index (BMI); in CKD5-ND with age, 8-OHdG, IL-6, high-sensitive C-reactive protein (hsCRP), and soluble vascular cell adhesion protein-1 (sVCAM-1); in CKD 3–4 with 8-OHdG and sVCAM-1; and in CKD 1–2 with age and sVCAM-1. In multivariate analysis, age (one standard deviation, 1-SD higher), malnutrition (subjective global assessment, SGA), oxidative stress (8-OHdG, 1-SD higher), and belonging to CKD5-ND, HD and PD cohorts associated with 1-SD higher pentosidine. In GENMOD, 1-SD higher pentosidine independently predicted all-cause mortality (relative risk, RR = 1.04; 95% confidence interval, CI, 1.01–1.08, p = 0.01) and CVD mortality (RR = 1.03; 95% CI, 1.01–1.06, p = 0.03) after adjusting for all confounders. Conclusions Plasma

Inverse associations between obesity indicators and thymic T-cell production levels in aging atomic-bomb survivors.

PubMed

Yoshida, Kengo; Nakashima, Eiji; Kubo, Yoshiko; Yamaoka, Mika; Kajimura, Junko; Kyoizumi, Seishi; Hayashi, Tomonori; Ohishi, Waka; Kusunoki, Yoichiro

2014-01-01

Reduction of the naive T-cell population represents a deteriorating state in the immune system that occurs with advancing age. In animal model studies, obesity compromises the T-cell immune system as a result of enhanced adipogenesis in primary lymphoid organs and systemic inflammation. In this study, to test the hypothesis that obesity may contribute to the aging of human T-cell immunity, a thousand atomic-bomb survivors were examined for obesity status and ability to produce naive T cells, i.e., T-cell receptor excision circle (TREC) numbers in CD4 and CD8 T cells. The number of TRECs showed a strong positive correlation with naive T cell numbers, and lower TREC numbers were associated with higher age. We found that the TREC number was inversely associated with levels of obesity indicators (BMI, hemoglobin A1c) and serum CRP levels. Development of type-2 diabetes and fatty liver was also associated with lower TREC numbers. This population study suggests that obesity with enhanced inflammation is involved in aging of the human T-cell immune system. Given the fact that obesity increases the risk of numerous age-related diseases, attenuated immune competence is a possible mechanistic link between obesity and disease development among the elderly.

Inverse Associations between Obesity Indicators and Thymic T-Cell Production Levels in Aging Atomic-Bomb Survivors

PubMed Central

Yoshida, Kengo; Nakashima, Eiji; Kubo, Yoshiko; Yamaoka, Mika; Kajimura, Junko; Kyoizumi, Seishi; Hayashi, Tomonori; Ohishi, Waka; Kusunoki, Yoichiro

2014-01-01

Reduction of the naive T-cell population represents a deteriorating state in the immune system that occurs with advancing age. In animal model studies, obesity compromises the T-cell immune system as a result of enhanced adipogenesis in primary lymphoid organs and systemic inflammation. In this study, to test the hypothesis that obesity may contribute to the aging of human T-cell immunity, a thousand atomic-bomb survivors were examined for obesity status and ability to produce naive T cells, i.e., T-cell receptor excision circle (TREC) numbers in CD4 and CD8 T cells. The number of TRECs showed a strong positive correlation with naive T cell numbers, and lower TREC numbers were associated with higher age. We found that the TREC number was inversely associated with levels of obesity indicators (BMI, hemoglobin A1c) and serum CRP levels. Development of type-2 diabetes and fatty liver was also associated with lower TREC numbers. This population study suggests that obesity with enhanced inflammation is involved in aging of the human T-cell immune system. Given the fact that obesity increases the risk of numerous age-related diseases, attenuated immune competence is a possible mechanistic link between obesity and disease development among the elderly. PMID:24651652

Plasma cell gingivitis associated with inflammatory chelitis: a report on a rare case.

PubMed

Abhishek, Kandwal; Rashmi, Jindal

2013-07-01

Plasma cell gingivitis (PGC) is a rare disease of gingival tissues which is difficult to treat. It has a higher rate of reoccurrence and needs a detailed and careful analysis of etiology. Further, its association with chelitis is rare, only few cases have been reported and the condition with this presentation poses a diagnostic dilemma. This paper reports a 16 year old male with a complaint of bleeding and swelling of gingiva since 3 years. The gingival enlargement occurred on facial aspect of upper and lower anterior teeth involving attached gingival. He also presented with swelling of both lips which was recurrent and for the same duration of 3 years. Based on clinical features and histopathological findings, a diagnosis of plasma cell gingivitis with inflammatory chelitis was made. A detailed history of possible allergen exposure was taken and patch test was conducted to identify any such allergens. Other conditions were ruled out by blood investigation, detailed medical and drug history. A close collaboration between Periodontist and Dermatologist is essential to manage such a case.

Mitochondrial-Associated Cell Death Mechanisms Are Reset to an Embryonic-Like State in Aged Donor-Derived iPS Cells Harboring Chromosomal Aberrations

PubMed Central

Prigione, Alessandro; Hossini, Amir M.; Lichtner, Björn; Serin, Akdes; Fauler, Beatrix; Megges, Matthias; Lurz, Rudi; Lehrach, Hans; Zouboulis, Christos C.

2011-01-01

Somatic cells reprogrammed into induced pluripotent stem cells (iPSCs) acquire features of human embryonic stem cells (hESCs) and thus represent a promising source for cellular therapy of debilitating diseases, such as age-related disorders. However, reprogrammed cell lines have been found to harbor various genomic alterations. In addition, we recently discovered that the mitochondrial DNA of human fibroblasts also undergoes random mutational events upon reprogramming. Aged somatic cells might possess high susceptibility to nuclear and mitochondrial genome instability. Hence, concerns over the oncogenic potential of reprogrammed cells due to the lack of genomic integrity may hinder the applicability of iPSC-based therapies for age-associated conditions. Here, we investigated whether aged reprogrammed cells harboring chromosomal abnormalities show resistance to apoptotic cell death or mitochondrial-associated oxidative stress, both hallmarks of cancer transformation. Four iPSC lines were generated from dermal fibroblasts derived from an 84-year-old woman, representing the oldest human donor so far reprogrammed to pluripotency. Despite the presence of karyotype aberrations, all aged-iPSCs were able to differentiate into neurons, re-establish telomerase activity, and reconfigure mitochondrial ultra-structure and functionality to a hESC-like state. Importantly, aged-iPSCs exhibited high sensitivity to drug-induced apoptosis and low levels of oxidative stress and DNA damage, in a similar fashion as iPSCs derived from young donors and hESCs. Thus, the occurrence of chromosomal abnormalities within aged reprogrammed cells might not be sufficient to over-ride the cellular surveillance machinery and induce malignant transformation through the alteration of mitochondrial-associated cell death. Taken together, we unveiled that cellular reprogramming is capable of reversing aging-related features in somatic cells from a very old subject, despite the presence of genomic

Inhibition of Progenitor Dendritic Cell Maturation by Plasma from Patients with Peripartum Cardiomyopathy: Role in Pregnancy-associated Heart Disease

PubMed Central

Ellis, Jane E.; Ansari, Aftab A.; Fett, James D.; Carraway, Robert D.; Randall, Hugh W.; Mosunjac, Mario I.; Sundstrom, J. Bruce

2005-01-01

Dendritic cells (DCs) play dual roles in innate and adaptive immunity based on their functional maturity, and both innate and adaptive immune responses have been implicated in myocardial tissue remodeling associated with cardiomyopathies. Peripartum cardiomyopathy (PPCM) is a rare disorder which affects women within one month antepartum to five months postpartum. A high occurrence of PPCM in central Haiti (1 in 300 live births) provided the unique opportunity to study the relationship of immune activation and DC maturation to the etiology of this disorder. Plasma samples from two groups (n = 12) of age- and parity-matched Haitian women with or without evidence of PPCM were tested for levels of biomarkers of cardiac tissue remodeling and immune activation. Significantly elevated levels of GM-CSF, endothelin-1, proBNP and CRP and decreased levels of TGF- were measured in PPCM subjects relative to controls. Yet despite these findings, in vitro maturation of normal human cord blood derived progenitor dendritic cells (CBDCs) was significantly reduced (p < 0.001) in the presence of plasma from PPCM patients relative to plasma from post-partum control subjects as determined by expression of CD80, CD86, CD83, CCR7, MHC class II and the ability of these matured CBDCs to induce allo-responses in PBMCs. These results represent the first findings linking inhibition of DC maturation to the dysregulation of normal physiologic cardiac tissue remodeling during pregnancy and the pathogenesis of PPCM. PMID:16584112

A Gestational Profile of Placental Exosomes in Maternal Plasma and Their Effects on Endothelial Cell Migration

PubMed Central

Salomon, Carlos; Torres, Maria Jose; Kobayashi, Miharu; Scholz-Romero, Katherin; Sobrevia, Luis; Dobierzewska, Aneta; Illanes, Sebastian E.; Mitchell, Murray D.; Rice, Gregory E.

2014-01-01

Studies completed to date provide persuasive evidence that placental cell-derived exosomes play a significant role in intercellular communication pathways that potentially contribute to placentation and development of materno-fetal vascular circulation. The aim of this study was to establish the gestational-age release profile and bioactivity of placental cell-derived exosome in maternal plasma. Plasma samples (n = 20 per pregnant group) were obtained from non-pregnant and pregnant women in the first (FT, 6–12 weeks), second (ST, 22–24 weeks) and third (TT, 32–38 weeks) trimester. The number of exosomes and placental exosome contribution were determined by quantifying immunoreactive exosomal CD63 and placenta-specific marker (PLAP), respectively. The effect of exosomes isolated from FT, ST and TT on endothelial cell migration were established using a real-time, live-cell imaging system (Incucyte). Exosome plasma concentration was more than 50-fold greater in pregnant women than in non-pregnant women (p<0.001). During normal healthy pregnancy, the number of exosomes present in maternal plasma increased significantly with gestational age by more that two-fold (p<0.001). Exosomes isolated from FT, ST and TT increased endothelial cell migration by 1.9±0.1, 1.6±0.2 and 1.3±0.1-fold, respectively compared to the control. Pregnancy is associated with a dramatic increase in the number of exosomes present in plasma and maternal plasma exosomes are bioactive. While the role of placental cell-derived exosome in regulating maternal and/or fetal vascular responses remains to be elucidated, changes in exosome profile may be of clinical utility in the diagnosis of placental dysfunction. PMID:24905832

TMEM106B gene polymorphism is associated with age at onset in granulin mutation carriers and plasma granulin protein levels

PubMed Central

Cruchaga, Carlos; Graff, Caroline; Chiang, Huei-Hsin; Wang, Jun; Hinrichs, Anthony L.; Spiegel, Noah; Bertelsen, Sarah; Mayo, Kevin; Norton, Joanne B.; Morris, John C.; Goate, Alison

2011-01-01

Objective A recent genome-wide association study for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP), identified rs1990622 (TMEM106B) as a risk factor for FTLD-TDP. In this study we tested whether rs1990622 is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy elderly individuals. Design Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier and a Cox proportional hazards model. Subjects We analyzed 50 affected and unaffected GRN mutation carriers from four previously reported FTLD-TDP families (HDDD1, FD1, HDDD2 and the Karolinska family). GRN plasma levels were also measured in 73 healthy, elderly individuals. Results The risk allele of rs1990622 is associated with a mean decrease of the age at onset of thirteen years (p=9.9×10−7), with lower plasma granulin levels in both healthy older adults (p = 4×10−4) and GRN mutation carriers (p=0.0027). Analysis of the HAPMAP database identified a non-synonymous single nucleotide polymorphism, rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622. Conclusions The association of rs1990622 with AAO explains, in part, the wide range in the age at onset of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer’s disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN. PMID:21220649

Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels.

PubMed

Cruchaga, Carlos; Graff, Caroline; Chiang, Huei-Hsin; Wang, Jun; Hinrichs, Anthony L; Spiegel, Noah; Bertelsen, Sarah; Mayo, Kevin; Norton, Joanne B; Morris, John C; Goate, Alison

2011-05-01

To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association. Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model. Alzheimer's Disease Research Center. Subjects  We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals. Age at onset and GRN plasma levels. The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622. The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.

Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study.

PubMed

Neuhouser, Marian L; Cheng, Ting-Yuan David; Beresford, Shirley A A; Brown, Elissa; Song, Xiaoling; Miller, Joshua W; Zheng, Yingye; Thomson, Cynthia A; Shikany, James M; Vitolins, Mara Z; Rohan, Thomas; Green, Ralph; Ulrich, Cornelia M

2015-08-15

The relationship between folate and colorectal cancer (CRC) risk is unclear. We investigated the association of two biomarkers of folate status, plasma folate and red blood cell (RBC) folate, with CRC risk using a nested case-control design in the Women's Health Initiative Observational Study. Postmenopausal women (n = 93,676) aged 50-79 years were enrolled in the Women's Health Initiative Observational Study (1993-1998). A fasting blood draw and extensive health, dietary and lifestyle data were collected upon enrollment. Through 2008, 988 incident CRC cases were reported and confirmed with medical records adjudication. Cases and controls were matched on age (± 3 years), enrollment date (± 1 year), race/ethnicity, blood draw date (± 6 months) and hysterectomy status. Plasma and RBC folate were determined by radio assay. Folate biomarker values were divided into quartiles, and conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for the associations of folate with total CRC, by tumor site and by stage at diagnosis. Additional analyses examined whether risks varied across time periods corresponding to the United States folic acid fortification policy: prefortification (1994-1995), perifortification (1996-1997) and postfortification (1998). ORs for overall CRC risk comparing Q4 vs. Q1 were 0.91 (95% CI 0.67-1.24) and 0.91 (95% CI 0.67-1.23) for RBC and plasma folate, respectively. There were no changes in risk attributable to food supply fortification. These results do not support an overall association of folate with CRC risk and suggest that folic acid fortification of the US food supply did not alter the associations in these postmenopausal women. © 2015 UICC.

Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity.

PubMed

Kriete, Andres; Mayo, Kelli L; Yalamanchili, Nirupama; Beggs, William; Bender, Patrick; Kari, Csaba; Rodeck, Ulrich

2008-07-16

Chronic inflammation is a well-known corollary of the aging process and is believed to significantly contribute to morbidity and mortality of many age-associated chronic diseases. However, the mechanisms that cause age-associated inflammatory changes are not well understood. Particularly, the contribution of cell stress responses to age-associated inflammation in 'non-inflammatory' cells remains poorly defined. The present cross-sectional study focused on differences in molecular signatures indicative of inflammatory states associated with biological aging of human fibroblasts from donors aged 22 to 92 years. Gene expression profiling revealed elevated steady-state transcript levels consistent with a chronic inflammatory state in fibroblast cell-strains obtained from older donors. We also observed enhanced NF-kappaB DNA binding activity in a subset of strains, and the NF-kappaB profile correlated with mRNA expression levels characteristic of inflammatory processes, which include transcripts coding for cytokines, chemokines, components of the complement cascade and MHC molecules. This intrinsic low-grade inflammatory state, as it relates to aging, occurs in cultured cells irrespective of the presence of other cell types or the in vivo context. Our results are consistent with the view that constitutive activation of inflammatory pathways is a phenomenon prevalent in aged fibroblasts. It is possibly part of a cellular survival process in response to compromised mitochondrial function. Importantly, the inflammatory gene expression signature described here is cell autonomous, i.e. occurs in the absence of prototypical immune or pro-inflammatory cells, growth factors, or other inflammatory mediators.

PTSD is associated with an increase in aged T cell phenotypes in adults living in Detroit

PubMed Central

Aiello, Allison E.; Dowd, Jennifer B.; Jayabalasingham, Bamini; Feinstein, Lydia; Uddin, Monica; Simanek, Amanda M.; Cheng, Caroline K.; Galea, Sandro; Wildman, Derek E.; Koenen, Karestan; Pawelec, Graham

2016-01-01

Background Psychosocial stress is thought to play a key role in the acceleration of immunological aging. This study investigated the relationship between lifetime and past-year history of post-traumatic stress disorder (PTSD) and the distribution of T cell phenotypes thought to be characteristic of immunological aging. Methods Data were from 85 individuals who participated in the community-based Detroit Neighborhood Health Study. Immune markers assessed included the CD4:CD8 ratio, the ratio of late-differentiated effector (CCR7-CD45RA+CD27-CD28-) to naïve (CCR7+CD45RA+CD27+CD28+) T cells, the percentage of KLRG1-expressing cells, and the percentage of CD57-expressing cells. Results In models adjusted for age, gender, race/ethnicity, education, smoking status, and medication use, we found that past-year PTSD was associated with statistically significant differences in the CD8+ T cell population, including a higher ratio of late-differentiated effector to naïve T cells, a higher percentage of KLRG1+ cells, and a higher percentage of CD57+ cells. The percentage of CD57+ cells in the CD4 subset was also significantly higher and the CD4:CD8 ratio significantly lower among individuals who had experienced past-year PTSD. Lifetime PTSD was also associated with differences in several parameters of immune aging. Conclusions PTSD is associated with an aged immune phenotype and should be evaluated as a potential catalyzer of accelerated immunological aging in future studies. PMID:26894484

Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

PubMed Central

Castellano, Joseph M.; Mosher, Kira I.; Abbey, Rachelle J.; McBride, Alisha A.; James, Michelle L.; Berdnik, Daniela; Shen, Jadon C.; Zou, Bende; Xie, Xinmin S.; Tingle, Martha; Hinkson, Izumi V.; Angst, Martin S.; Wyss-Coray, Tony

2017-01-01

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation1, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation2, 3, 4 and downregulated in the aged brain5, 6, 7, 8. In addition to revitalizing other aged tissues9, 10, 11, 12, 13, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters14, 15, 16, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown17. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high

Associations of plasma leptin to clinical manifestations in reproductive aged female patients with panic disorder.

PubMed

Masdrakis, Vasilios G; Papageorgiou, Charalambos; Markianos, Manolis

2017-09-01

Preclinical studies suggest the implication of the adipocyte hormone leptin in anxiety and fear processes. We explored for potential differences regarding plasma leptin, cortisol and the ratio leptin/Body Mass Index (BMI) between 27 medication-free female patients with Panic Disorder (PD) and 42 age-matched female controls, and for potential associations between plasma leptin and psychometric evaluations including number of panic attacks during last week, Clinical Global Impression-Severity of Illness (CGI-S) and Symptoms Checklist-90-Revised (SCL-90-R). Cortisol levels showed no differences between patients and controls, or correlations to leptin or to any clinical features. Both groups demonstrated a strong positive correlation between leptin and BMI and similar leptin and leptin/BMI, despite patients' lower BMI. However, patients -but not controls- demonstrated significant negative correlations of leptin to the 'somatization', 'anxiety', and 'phobic anxiety' SCL-90-R subscales. Moreover, there was a significant negative correlation of leptin and of leptin/BMI ratio to the number of panic attacks during last week, while higher CGI-S was associated with lower leptin/BMI ratio. Our results, limited to PD female patients, suggest that lower leptin serum levels are significantly associated with greater severity of psychopathological manifestations, including number of panic attacks, symptoms of somatization, anxiety and phobic anxiety and overall clinical presentation. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Changes in Circulating B Cell Subsets Associated with Aging and Acute SIV Infection in Rhesus Macaques.

PubMed

Chang, W L William; Gonzalez, Denise F; Kieu, Hung T; Castillo, Luis D; Messaoudi, Ilhem; Shen, Xiaoying; Tomaras, Georgia D; Shacklett, Barbara L; Barry, Peter A; Sparger, Ellen E

2017-01-01

Aging and certain viral infections can negatively impact humoral responses in humans. To further develop the nonhuman primate (NHP) model for investigating B cell dynamics in human aging and infectious disease, a flow cytometric panel was developed to characterize circulating rhesus B cell subsets. Significant differences between human and macaque B cells included the proportions of cells within IgD+ and switched memory populations and a prominent CD21-CD27+ unswitched memory population detected only in macaques. We then utilized the expanded panel to analyze B cell alterations associated with aging and acute simian immunodeficiency virus (SIV) infection in the NHP model. In the aging study, distinct patterns of B cell subset frequencies were observed for macaques aged one to five years compared to those between ages 5 and 30 years. In the SIV infection study, B cell frequencies and absolute number were dramatically reduced following acute infection, but recovered within four weeks of infection. Thereafter, the frequencies of activated memory B cells progressively increased; these were significantly correlated with the magnitude of SIV-specific IgG responses, and coincided with impaired maturation of anti-SIV antibody avidity, as previously reported for HIV-1 infection. These observations further validate the NHP model for investigation of mechanisms responsible for B cells alterations associated with immunosenescence and infectious disease.

Association between cell-bound blood amyloid-β(1-40) levels and hippocampus volume.

PubMed

Sotolongo-Grau, Oscar; Pesini, Pedro; Valero, Sergi; Lafuente, Asunción; Buendía, Mar; Pérez-Grijalba, Virginia; José, Itziar San; Ibarria, Marta; Tejero, Miguel A; Giménez, Joan; Hernández, Isabel; Tárraga, Lluís; Ruiz, Agustín; Boada, Mercé; Sarasa, Manuel

2014-01-01

The identification of early, preferably presymptomatic, biomarkers and true etiologic factors for Alzheimer's disease (AD) is the first step toward establishing effective primary and secondary prevention programs. Consequently, the search for a relatively inexpensive and harmless biomarker for AD continues. Despite intensive research worldwide, to date there is no definitive plasma or blood biomarker indicating high or low risk of conversion to AD. Magnetic resonance imaging and β-amyloid (Aβ) levels in three blood compartments (diluted in plasma, undiluted in plasma and cell-bound) were measured in 96 subjects (33 with mild cognitive impairment, 14 with AD and 49 healthy controls). Pearson correlations were completed between 113 regions of interest (ROIs) (45 subcortical and 68 cortical) and Aβ levels. Pearson correlation analyses adjusted for the covariates age, sex, apolipoprotein E (ApoE), education and creatinine levels showed neuroimaging ROIs were associated with Aβ levels. Two statistical methods were applied to study the major relationships identified: (1) Pearson correlation with phenotype added as a covariate and (2) a meta-analysis stratified by phenotype. Neuroimaging data and plasma Aβ measurements were taken from 630 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects to be compared with our results. The left hippocampus was the brain region most correlated with Aβ(1-40) bound to blood cell pellets (partial correlation (pcor) = -0.37, P = 0.0007) after adjustment for the covariates age, gender and education, ApoE and creatinine levels. The correlation remained almost the same (pcor = -0.35, P = 0.002) if phenotype is also added as a covariate. The association between both measurements was independent of cognitive status. The left hemisphere entorhinal cortex also correlated with Aβ(1-40) cell-bound fraction. AB128 and ADNI plasma Aβ measurements were not related to any brain morphometric measurement. Association of

FLOCK cluster analysis of plasma cell flow cytometry data predicts bone marrow involvement by plasma cell neoplasia.

PubMed

Dorfman, David M; LaPlante, Charlotte D; Li, Betty

2016-09-01

We analyzed plasma cell populations in bone marrow samples from 353 patients with possible bone marrow involvement by a plasma cell neoplasm, using FLOCK (FLOw Clustering without K), an unbiased, automated, computational approach to identify cell subsets in multidimensional flow cytometry data. FLOCK identified discrete plasma cell populations in the majority of bone marrow specimens found by standard histologic and immunophenotypic criteria to be involved by a plasma cell neoplasm (202/208 cases; 97%), including 34 cases that were negative by standard flow cytometric analysis that included clonality assessment. FLOCK identified discrete plasma cell populations in only a minority of cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (38/145 cases; 26%). Interestingly, 55% of the cases negative by standard analysis, but containing a FLOCK-identified discrete plasma cell population, were positive for monoclonal gammopathy by serum protein electrophoresis and immunofixation. FLOCK-identified and quantitated plasma cell populations accounted for 3.05% of total cells on average in cases positive for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria, and 0.27% of total cells on average in cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (p<0.0001; area under the curve by ROC analysis=0.96). The presence of a FLOCK-identified discrete plasma cell population was predictive of the presence of plasma cell neoplasia with a sensitivity of 97%, compared with only 81% for standard flow cytometric analysis, and had specificity of 74%, PPV of 84% and NPV of 95%. FLOCK analysis, which has been shown to provide useful diagnostic information for evaluating patients with suspected systemic mastocytosis, is able to identify neoplastic plasma cell populations analyzed by flow cytometry, and may be helpful in the diagnostic

Dysmegakaryocytopoiesis and maintaining platelet count in patients with plasma cell neoplasm.

PubMed

Mair, Yasmin; Zheng, Yan; Cai, Donghong

2013-05-01

Dysmegakaryocytopoiesis in patients with the plasma cell neoplasm (PCN) is rarely discussed in the literature. The puzzling phenomenon, which PCN patients maintaining normal platelet count even when the marrow is mostly replaced by plasma cells, is hardly explored. This study was aimed to determine the frequency of dysmegakaryocytopoiesis in PCN and the relationships between bone marrow (BM) plasma cell percentage, plasma cell immunomarkers, the severity of dysmegakaryocytopoiesis, and peripheral blood platelet count in PCN. We randomly selected 16 cases of PCN, among which 4 were with monoclonal gammopathy of undetermined significance and 12 were with plasma cell myeloma. OUR STUDY SHOWED THAT: (1) Dysmegakaryocytopoiesis was present in all the selected cases of PCN and its severity was not correlated with the percentage of the plasma cells in BM; (2) almost all patients maintained normal platelet count even when BM was mostly replaced by plasma cells; (3) immunomarkers of the neoplastic plasma cells were not associated with dysmegakaryocytopoiesis or maintaining of platelet count. The possible mechanisms behind dysmegakaryocytopoiesis and maintaining of platelet count were also discussed. Despite the universal presence of dysmegakaryocytopoiesis in PCN, the platelet count is maintained at normal range.

A high plasma: red blood cell transfusion ratio during liver transplantation is associated with decreased blood utilization.

PubMed

Pagano, M B; Metcalf, R A; Hess, J R; Reyes, J; Perkins, J D; Montenovo, M I

2018-04-01

During massive transfusion, the volume ratio of administered plasma (PL Vol) to red blood cell (RBC Vol) appears to be associated with reduced blood utilization and improved survival. The aim of this study was to evaluate the optimal component ratio in the setting of liver transplantation. This is a retrospective chart review of patients who underwent liver transplantation and received at least 500 ml of red blood cells from January 2013 through December 2015. Kernel smoothing analysis determined the proper component ratios to evaluate were a ≥0·85:1 ratio (high) to a ≤0·85:1 ratio (low). Two groups, plasma volume to RBC volume (PL Vol/RBC Vol) and plasma contained in the platelet units added to the plasma calculation [PL + PLT (platelet)] Vol/RBC Vol, were used to evaluate the component ratios. A total of 188 patients were included in the analysis. In the PL Vol/RBC Vol evaluation, a low ratio revealed that 1238 ml (977-1653 ml) (P < 0·0001) and 1178 ml (747-1178) (P < 0·0001) of RBC were used in excess compared to the high ratio, in the univariable and multivariable analysis, respectively. In the PL +PLT Vol/RBC Vol evaluation, a low ratio used 734 ml (193-1275) (P = 0·008) and 886 ml (431-1340) (P < 0·0001) of RBC in excess when compared to high ratio in the univariable and multivariable analysis, respectively. In patients undergoing liver transplantation, the transfusion of plasma to RBC ratio ≥0·85 was associated with decreased need of RBC transfusions. © 2018 International Society of Blood Transfusion.

Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age

PubMed Central

Desta, Z; Kreutz, Y; Nguyen, AT; Li, L; Skaar, T; Kamdem, LK; Henry, NL; Hayes, DF; Storniolo, AM; Stearns, V; Hoffmann, E; Tyndale, RF; Flockhart, DA

2013-01-01

The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. plasma letrozole concentrations showed high interpatient variability (>10-fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects. PMID:21975350

Radiation- and Age-Associated Changes in Peripheral Blood Dendritic Cell Populations among Aging Atomic Bomb Survivors in Japan.

PubMed

Kajimura, Junko; Lynch, Heather E; Geyer, Susan; French, Benjamin; Yamaoka, Mika; Shterev, Ivo D; Sempowski, Gregory D; Kyoizumi, Seishi; Yoshida, Kengo; Misumi, Munechika; Ohishi, Waka; Hayashi, Tomonori; Nakachi, Kei; Kusunoki, Yoichiro

2017-11-30

Previous immunological studies in atomic bomb survivors have suggested that radiation exposure leads to long-lasting changes, similar to immunological aging observed in T-cell-adaptive immunity. However, to our knowledge, late effects of radiation on dendritic cells (DCs), the key coordinators for activation and differentiation of T cells, have not yet been investigated in humans. In the current study, we hypothesized that numerical and functional decreases would be observed in relationship to radiation dose in circulating conventional DCs (cDCs) and plasmacytoid DCs (pDCs) among 229 Japanese A-bomb survivors. Overall, the evidence did not support this hypothesis, with no overall changes in DCs or functional changes observed with radiation dose. Multivariable regression analysis for radiation dose, age and gender effects revealed that total DC counts as well as subpopulation counts decreased in relationship to increasing age. Further analyses revealed that in women, absolute numbers of pDCs showed significant decreases with radiation dose. A hierarchical clustering analysis of gene expression profiles in DCs after Toll-like receptor stimulation in vitro identified two clusters of participants that differed in age-associated expression levels of genes involved in antigen presentation and cytokine/chemokine production in cDCs. These results suggest that DC counts decrease and expression levels of gene clusters change with age. More than 60 years after radiation exposure, we also observed changes in pDC counts associated with radiation, but only among women.

Radiation- and Age-Associated Changes in Peripheral Blood Dendritic Cell Populations among Aging Atomic Bomb Survivors in Japan.

PubMed

Kajimura, Junko; Lynch, Heather E; Geyer, Susan; French, Benjamin; Yamaoka, Mika; Shterev, Ivo D; Sempowski, Gregory D; Kyoizumi, Seishi; Yoshida, Kengo; Misumi, Munechika; Ohishi, Waka; Hayashi, Tomonori; Nakachi, Kei; Kusunoki, Yoichiro

2018-01-01

Previous immunological studies in atomic bomb survivors have suggested that radiation exposure leads to long-lasting changes, similar to immunological aging observed in T-cell-adaptive immunity. However, to our knowledge, late effects of radiation on dendritic cells (DCs), the key coordinators for activation and differentiation of T cells, have not yet been investigated in humans. In the current study, we hypothesized that numerical and functional decreases would be observed in relationship to radiation dose in circulating conventional DCs (cDCs) and plasmacytoid DCs (pDCs) among 229 Japanese A-bomb survivors. Overall, the evidence did not support this hypothesis, with no overall changes in DCs or functional changes observed with radiation dose. Multivariable regression analysis for radiation dose, age and gender effects revealed that total DC counts as well as subpopulation counts decreased in relationship to increasing age. Further analyses revealed that in women, absolute numbers of pDCs showed significant decreases with radiation dose. A hierarchical clustering analysis of gene expression profiles in DCs after Toll-like receptor stimulation in vitro identified two clusters of participants that differed in age-associated expression levels of genes involved in antigen presentation and cytokine/chemokine production in cDCs. These results suggest that DC counts decrease and expression levels of gene clusters change with age. More than 60 years after radiation exposure, we also observed changes in pDC counts associated with radiation, but only among women.

Leveraging cell type specific regulatory regions to detect SNPs associated with tissue factor pathway inhibitor plasma levels.

PubMed

Dennis, Jessica; Medina-Rivera, Alejandra; Truong, Vinh; Antounians, Lina; Zwingerman, Nora; Carrasco, Giovana; Strug, Lisa; Wells, Phil; Trégouët, David-Alexandre; Morange, Pierre-Emmanuel; Wilson, Michael D; Gagnon, France

2017-07-01

Tissue factor pathway inhibitor (TFPI) regulates the formation of intravascular blood clots, which manifest clinically as ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). TFPI plasma levels are heritable, but the genetics underlying TFPI plasma level variability are poorly understood. Herein we report the first genome-wide association scan (GWAS) of TFPI plasma levels, conducted in 251 individuals from five extended French-Canadian Families ascertained on VTE. To improve discovery, we also applied a hypothesis-driven (HD) GWAS approach that prioritized single nucleotide polymorphisms (SNPs) in (1) hemostasis pathway genes, and (2) vascular endothelial cell (EC) regulatory regions, which are among the highest expressers of TFPI. Our GWAS identified 131 SNPs with suggestive evidence of association (P-value < 5 × 10 -8 ), but no SNPs reached the genome-wide threshold for statistical significance. Hemostasis pathway genes were not enriched for TFPI plasma level associated SNPs (global hypothesis test P-value = 0.147), but EC regulatory regions contained more TFPI plasma level associated SNPs than expected by chance (global hypothesis test P-value = 0.046). We therefore stratified our genome-wide SNPs, prioritizing those in EC regulatory regions via stratified false discovery rate (sFDR) control, and reranked the SNPs by q-value. The minimum q-value was 0.27, and the top-ranked SNPs did not show association evidence in the MARTHA replication sample of 1,033 unrelated VTE cases. Although this study did not result in new loci for TFPI, our work lays out a strategy to utilize epigenomic data in prioritization schemes for future GWAS studies. © 2017 WILEY PERIODICALS, INC.

[Associations of insulin resistance and pancreatic beta-cell function with plasma glucose level in type 2 diabetes].

PubMed

Nian, Xiaoping; Sun, Gaisheng; Dou, Chunmei; Hou, Hongbo; Fan, Xiuping; Yu, Hongmei; Ma, Ling; He, Bingxian

2002-06-10

To investigate the influence of insulin resistance and pancreatic beta-cell function on plasma glucose level in type 2 diabetes so as to provide theoretical basis for reasonable selection of hypoglycemic agents. The plasma non-specific insulin (NSINS), true insulin (TI) and glucose in eight-one type 2 diabetics, 38 males and 43 females, with a mean age of 53 years, were examined 0, 30, 60 and 120 minutes after they had 75 grams of instant noodles. The patients were divided into two groups according to their fasting plasma glucose (FPG): group A (FPG < 8.89 mmol/L) and group B (FPG> = 8.89 mmol/L). The insulin resistance was evaluated by HOMA-IR, the beta-cell function was evaluated by HOMA-beta formula and the formula deltaI(30)/deltaG(30) = (deltaI(30)-deltaI(0))/(deltaG(30)-deltaG(0)). The insulin area under curve (INSAUC) was evaluated by the formula INSAUC=FINS/2+INS(30)+INS(60)+INS(120)/2. The mean FPG was 6.23 mmol/L in group A and 12.6 mmol/L in group B. PG2H was 11.7 mmol/L in group A and 19.2 mmol/L in group B. The TI levels in group B at 0, 30, 60, 120 min during standard meal test were significantly higher than those in group A: 6.15 +/- 1.06 vs 4.77 +/- 1.06, 9.76 +/- 1.1 vs 5.88 +/- 1.1,14.68 +/- 1.11 vs 6.87 +/- 1.1 and 17.13 +/- 1.12 vs 8.0 +/- 1.1 microU/dl (all P< 0.01). The NSINS showed the same trend. The insulin resistance in group B was 1.5 times that in group A. With the insulin resistance adjusted, the beta cell function in group A was 5 to 6 times that in group B. The INSAUC in group A was 1.66 times larger than that in group B, especially the INSAUC for true insulin (2 times larger). The contribution of insulin resistance and beta cell function to PG2H was half by half in group A and 1:8 in group B. beta cell function calculated by insulin (Homa-beta) explained 41% of the plasma glucose changes in group A and 54% of the plasma glucose changes in group B. The contribution of insulin deficiency to plasma glocose was 3.3.times that of insulin

Involvement of blood mononuclear cells in the infertility, age-associated diseases and cancer treatment

PubMed Central

Bukovsky, Antonin

2016-01-01

Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system (TCS), where they exhibit morphostatic function by stimulating proliferation of tissue stem cells followed by cellular differentiation, that is stopped after attaining the proper functional stage, which differs among various tissue types. Therefore, the term immune and morphostatic system (IMS) should be implied. The TCS-mediated morphostasis also consists of vascular pericytes controlled by autonomic innervation, which is regulating the quantity of distinct tissues in vivo. Lack of proper differentiation of tissue cells by TCS causes either tissue underdevelopment, e.g., muscular dystrophy, or degenerative functional failures, e.g., type 1 diabetes and age-associated diseases. With the gradual IMS regression after 35 years of age the gonadal infertility develops, followed by a growing incidence of age-associated diseases and cancers. Without restoring an altered TCS function in a degenerative disease, the implantation of tissue-specific stem cells alone by regenerative medicine can not be successful. Transfused young blood could temporarily restore fertility to enable parenthood. The young blood could also temporarily alleviate aging diseases, and this can be extended by substances inducing IMS regeneration, like the honey bee propolis. The local and/or systemic use of honey bee propolis stopped hair and teeth loss, regressed varicose veins, improved altered hearing, and lowered high blood pressure and sugar levels. Complete regression of stage IV ovarian cancer with liver metastases after a simple elaborated immunotherapy is also reported. PMID:28074124

Age-associated Epstein–Barr virus-specific T cell responses in seropositive healthy adults

PubMed Central

Cárdenas Sierra, D; Vélez Colmenares, G; Orfao de Matos, A; Fiorentino Gómez, S; Quijano Gómez, S M

2014-01-01

Epstein–Barr virus (EBV) is present in 95% of the world's adult population. The immune response participates in immune vigilance and persistent infection control, and this condition is maintained by both a good quality (functionality) and quantity of specific T cells throughout life. In the present study, we evaluated EBV-specific CD4+ and CD8+ T lymphocyte responses in seropositive healthy individuals younger and older than 50 years of age. The assessment comprised the frequency, phenotype, functionality and clonotypic distribution of T lymphocytes. We found that in both age groups a similar EBV-specific T cell response was found, with overlapping numbers of tumour necrosis factor (TNF)-α+ T lymphocytes (CD4+ and CD8+) within the memory and effector cell compartments, in addition to monofunctional and multi-functional T cells producing interleukin (IL)-2 and/or interferon (IFN)-γ. However, individuals aged more than 50 years showed significantly higher frequencies of IL-2-producing CD4+ T lymphocytes in association with greater production of soluble IFN-γ, TNF-α and IL-6 than subjects younger than 50 years. A polyclonal T cell receptor (TCR)-variable beta region (Vβ) repertoire exists in both age groups under basal conditions and in response to EBV; the major TCR families found in TNF-α+/CD4+ T lymphocytes were Vβ1, Vβ2, Vβ17 and Vβ22 in both age groups, and the major TCR family in TNF-α+/CD8+ T cells was Vβ13·1 for individuals younger than 50 years and Vβ9 for individuals aged more than 50 years. Our findings suggest that the EBV-specific T cell response (using a polyclonal stimulation model) is distributed throughout several T cell differentiation compartments in an age-independent manner and includes both monofunctional and multi-functional T lymphocytes. PMID:24666437

Age- and gender-related alteration in plasma advanced oxidation protein products (AOPP) and glycosaminoglycan (GAG) concentrations in physiological ageing.

PubMed

Komosinska-Vassev, Katarzyna; Olczyk, Pawel; Winsz-Szczotka, Katarzyna; Kuznik-Trocha, Kornelia; Klimek, Katarzyna; Olczyk, Krystyna

2012-02-13

The authors studied the role of increased oxidative stress in the development of oxidative protein damage and extracellular matrix (ECM) components in ageing. The age- and gender-associated disturbances in connective tissue metabolism were evaluated by the plasma chondroitin sulphated glycosaminoglycans (CS-GAG) and non-sulphated GAG-hyaluronan (HA) measurements. Plasma concentration of advanced oxidation protein products (AOPP) was analysed in order to assess oxidative protein damage and evaluate the possible deleterious role of oxidative phenomenon on tissue proteoglycans' metabolism during the physiological ageing process. Sulphated and non-sulphated GAGs as well as AOPP were quantified in plasma samples from 177 healthy volunteers. A linear age-related decline of plasma CS-GAG level was found in this study (r=-0.46; p<0.05). In contrast, HA concentrations rise gradually with age (r=0.44; p<0.05) in plasma samples. For both ECM components, the observed differences were not gender-specific. A strong age-dependent relationship has been shown in regard to AOPP. AOPP levels significantly increased with age (r=0.63; p<0.05), equally strongly in both men (r=0.69; p<0.05) and women (r=0.57; p<0.05) during physiological ageing. A significant correlation was found between the concentrations of AOPP and both CS-GAG (r=-0.31; p<0.05) and HA (r=0.33; p<0.05). Proceeding with age changes in the ECM are reflected by CS-GAG and HA plasma levels. Strong correlations between AOPP and ECM components indicate that oxidative stress targets protein and non-protein components of the connective tissue matrix during human ageing.

Evaluation of the Efficacy of the Plasma Pencil Against Cancer Cells

NASA Astrophysics Data System (ADS)

Mohades, Soheila; Barekzi, Nazir; Razavi, Hamid; Laroussi, Mounir

2014-10-01

The plasma pencil generates low temperature and atmospheric pressure plasma. To generate the plasma, high voltage pulses with short width (from nanosecond to microsecond) are applied to a noble gas. The working gas can be helium, argon or a mixture of these with air or oxygen. Generating plasma with helium provides a tolerable temperature for biological cells and tissues. Diagnostic measurements on the plasma plume has revealed the presence of active agents such as reactive oxygen species (ROS) and nitrogen reactive species (RNS), which are known to have biological implications. Recently, low temperature plasma has drawn attention to its potential in cancer therapy. In our lab, the plasma pencil has been used to treat leukemia, prostate and epithelial cancer cells. The cancer cell line used here is the SCaBER (ATCC®HTB3™) cell line originating from a human bladder cancer. The results indicate that specific species induce the molecular mechanisms associated with cell death. The death of cells after plasma treatment will be studied using assays, such as DNA laddering and Caspase-3 activation, to elucidate the mechanism of the apoptotic or necrotic pathways.

Age-dependent changes in plasma biochemistry of yellow-legged gulls (Larus cachinnans).

PubMed

Alonso-Alvarez, Carlos

2005-04-01

The study of avian plasma chemistry is providing useful reference values for the management of endangered and game species, supporting veterinarians in their diagnostics, and also bringing to light relevant physiological adaptations during periods of food-shortage. Age is an important source of variability for plasma chemistry. Here I report plasma chemistry of yellow-legged gulls Larus cachinnans from different ages, between post-independence and adulthood, a 5-year interval. Increase in plasma cholesterol concentration and decreases in uric acid, inorganic phosphorus and alkaline phosphatase values were seen. Body mass corrected by body size (i.e. body condition) increased with age, plasma cholesterol being positively correlated in females, but not in males. Moreover, cholesterol was also positively correlated to gonad size in both sexes. Long-term developmental changes in this species, such as gonad development and the acquisition of an optimal body mass for reproduction, could explain these findings. Finally, inorganic phosphorus and alkaline phosphatase, both traditionally related to osteogenesis, were not associated to deferred skull ossification, as originally was suggested in other species.

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases.

PubMed

Kubben, Nard; Misteli, Tom

2017-10-01

Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson-Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.

Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging.

PubMed

Lin, Jonathan B; Sene, Abdoulaye; Santeford, Andrea; Fujiwara, Hideji; Sidhu, Rohini; Ligon, Marianne M; Shankar, Vikram A; Ban, Norimitsu; Mysorekar, Indira U; Ory, Daniel S; Apte, Rajendra S

2018-06-11

Macrophage aging is pathogenic in numerous diseases, including age-related macular degeneration (AMD), a leading cause of blindness in older adults. Although prior studies have explored the functional consequences of macrophage aging, less is known about its cellular basis or what defines the transition from physiologic aging to disease. Here, we show that despite their frequent self-renewal, macrophages from old mice exhibited numerous signs of aging, such as impaired oxidative respiration. Transcriptomic profiling of aged murine macrophages revealed dysregulation of diverse cellular pathways, especially in cholesterol homeostasis, that manifested in altered oxysterol signatures. Although the levels of numerous oxysterols in human peripheral blood mononuclear cells and plasma exhibited age-associated changes, plasma 24-hydroxycholesterol levels were specifically associated with AMD. These novel findings demonstrate that oxysterol levels can discriminate disease from physiologic aging. Furthermore, modulation of cholesterol homeostasis may be a novel strategy for treating age-associated diseases in which macrophage aging is pathogenic. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Cell population data in neonates: differences by age group and associations with perinatal factors.

PubMed

Lee, J; Kim, S Y; Lee, W; Han, K; Sung, I K

2015-10-01

Cell population data (CPD) describe physical parameters of white blood cell subpopulations and are reported to be of some value in the diagnosis of sepsis in neonates. Before using the CPD for diagnosing sepsis, the baseline features of the CPD distribution in healthy neonates should be clarified. The aim of this study was to compare the CPD distributions of healthy neonates and other age groups and to identify perinatal factors that are associated with changes in the CPD distribution of healthy neonates. The CPD distribution of 69 samples from term neonates was compared with adolescents and adults. The CPD distribution of 163 samples from healthy neonates was analyzed in association with perinatal factors, including gestational age, chronologic age, birthweight, delivery mode, premature rupture of membranes, diabetes, and pregnancy-induced hypertension. The CPD distribution for term neonates was significantly different from those in adolescents and adults. The mean lymphocyte volume showed a negative correlation with gestational age at birth (r = -0.305; P < 0.01). The mean neutrophil volume was smaller in the cesarean section group than in the normal delivery group. The small for gestational age (SGA) group had smaller mean neutrophil volume and mean monocyte volume than the appropriate for gestational age group. The CPD distribution of healthy neonates differed from those of adolescents or adults, and the differences were associated with gestational age, delivery mode, and being SGA. © 2015 John Wiley & Sons Ltd.

Extranodal rosai-dorfman disease associated with increased numbers of immunoglobulin g4 plasma cells involving the colon: case report with literature review.

PubMed

Wimmer, Daniel B; Ro, Jae Y; Lewis, Annisa; Schwartz, Mary R; Caplan, Richard; Schwarz, Peter; Ayala, Alberto G

2013-07-01

A 49-year-old woman presented with fever, weight loss, night sweats, hematochezia, and acid reflux symptoms. Two large, firm cecal lesions were seen at colonoscopy, but multiple biopsies were inconclusive. The patient underwent a right hemicolectomy for a clinical diagnosis of colon cancer. Noncaseating granulomatous inflammation with background lymphocytes, plasma cells, and histiocytes exhibiting emperipolesis were identified. With these histologic features and immunoreactivity for S-100 protein and CD68, a diagnosis of Rosai-Dorfman disease was rendered. Other areas had storiform fibrosis admixed with numerous immunoglobulin G4 (IgG4)-positive plasma cells. Although a few preliminary reports have noted an increased number of IgG4-positive plasma cells in Rosai-Dorfman disease, the relationship between these 2 conditions is unclear. To our knowledge, this is the first case report of a possible association of colonic Rosai-Dorfman disease with an increased number of IgG4-positive plasma cells. Reviews of colonic Rosai-Dorfman disease and IgG4-related sclerosis are presented to heighten awareness of this rare presentation.

Latent associations of low serum amylase with decreased plasma insulin levels and insulin resistance in asymptomatic middle-aged adults

PubMed Central

2012-01-01

Background Low serum amylase is likely to be associated with obesity and metabolic abnormalities, which are often accompanied by impaired insulin action. However, it is unclear whether low serum amylase is associated with impaired insulin action in clinical settings. Therefore, we investigated the associations of low serum amylase with plasma insulin levels, and obesity-related parameters, including leptin. Research design and methods We measured serum amylase, plasma insulin, obesity-related parameters such as leptin, cardiometabolic risk factors, and anthropometric parameters in a cross-sectional study of 54 asymptomatic subjects (mean age 48.6 ± 7.6 years) who were not being treated for diabetes. Results Body mass index (BMI) and plasma glucose at 120 min after a 75-g oral glucose tolerance test (OGTT) were significantly higher in subjects with low serum amylase (< 60 IU/l, n = 21) than in those with normal-to-high serum amylase (n = 33) (P = 0.04 and P = 0.004, respectively). In univariate correlation analysis, serum amylase was significantly correlated with BMI alone (r = –0.39, P = 0.004). By contrast, multivariate logistic analysis showed that each 1-SD increase in quantitative insulin sensitivity check index, and each 1-SD decrease in plasma insulin OGTT at 0 and 60 min, homeostasis model assessment of insulin resistance (HOMA)-R, and HOMA-β were significantly associated with low serum amylase, particularly after adjusting for BMI. When subjects were divided into three groups according to HOMA-R, serum amylase levels were significantly lower in subjects with HOMA-R > 2.5 (n = 23) compared with subjects with HOMA-R 1.6–2.5 (n = 10) (61.1 ± 13.6 U/ml versus 76.9 ± 20.5 U/ml, Bonferroni test, P = 0.02), but not compared with subjects with HOMA-R<1.6 (n = 21; 62.7 ± 17.6 U/ml). Similar trends were observed when subjects were divided according to plasma leptin and fasting plasma

"Angular" plasma cell cheilitis.

PubMed

da Cunha Filho, Roberto Rheingantz; Tochetto, Lucas Baldissera; Tochetto, Bruno Baldissera; de Almeida, Hiram Larangeira; Lorencette, Nádia Aparecida; Netto, José Fillus

2014-03-17

Plasma cell cheilitis is an extremely rare disease, characterized by erythematous-violaceous, ulcerated and asymptomatic plaques, which evolve slowly. The histological characteristics include dermal infiltrate composed of mature plasmocytes. We report a case of Plasma cell angular cheilitis in a 58-year-old male, localized in the lateral oral commissure.

Induction of Immunogenic Cell Death with Non-Thermal Plasma for Cancer Immunotherapy

NASA Astrophysics Data System (ADS)

Lin, Abraham G.

Even with the recent advancements in cancer immunotherapy, treatments are still associated with debilitating side effects and unacceptable fail rates. Induction of immunogenic cell death (ICD) in tumors is a promising approach to cancer treatment that may overcome these deficiencies. Cells undergoing ICD pathways enhance the interactions between cancerous cells and immune cells of the patient, resulting in the generation of anti-cancer immunity. The goal of this therapy relies on the engagement and reestablishment of the patient's natural immune processes to target and eliminate cancerous cells systemically. The main objective of this research was to determine if non-thermal plasma could be used to elicit immunogenic cancer cell death for cancer immunotherapy. My hypothesis was that plasma induces immunogenic cancer cell death through oxidative stress pathways, followed by development of a specific anti-tumor immune response. This was tested by investigating the interactions between plasma and multiple cancerous cells in vitro and validating anti-tumor immune responses in vivo. Following plasma treatment, two surrogate ICD markers, secreted adenosine triphosphate (ATP) and surface exposed calreticulin (ecto-CRT), were emitted from all three cancerous cell lines tested: A549 lung carcinoma cell line, CNE-1 radiation-resistant nasopharyngeal cell line and CT26 colorectal cancer cell line. When these cells were co-cultured with macrophages, cells of the innate immune system, the tumoricidal activity of macrophages was enhanced, thus demonstrating the immunostimulatory activity of cells undergoing ICD. The underlying mechanisms of plasma-induced ICD were also evaluated. When plasma is generated, four major components are produced: electromagnetic fields, ultraviolet radiation, and charged and neutral reactive species. Of these, we determined that plasma-generated charged and short-lived reactive oxygen species (ROS) were the major effectors of ICD. Following plasma

Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS

PubMed Central

Nesheim, Nils; Ellem, Stuart; Dansranjavin, Temuujin; Hagenkötter, Christina; Berg, Elena; Schambeck, Rupert; Schuppe, Hans-Christian; Pilatz, Adrian; Risbridger, Gail; Weidner, Wolfgang

2018-01-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III (n = 50; median age 39.8, range 23–65) and age-matched controls (n = 61; median age 36.8, range 20–69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes (ESR1 and ESR2) in leukocytes isolated from blood (systemic regulation) and in somatic cells isolated from ejaculates (local regulation). We found elevated 17β-estradiol (E2) levels in seminal plasma, but not in blood plasma, that was significantly associated with CP/CPPS and impaired urinary tract symptoms. In ejaculated somatic cells of CP/CPPS patients we found that ESR1 and ESR2 were both significantly higher methylated in CpG-promoters and expressionally down-regulated in comparison to controls. Mast cells are reported to contribute to CP/CPPS and are estrogen responsive. Consistent with this, we found that E2 –treatment of human mast cell lines (HMC-1 and LAD2) resulted in altered cytokine and chemokine expression. Interestingly, in HMC-1 cells, possessing epigenetically inactivated ESR1 and ESR2, E2 –treatment led to a reduced transcription of a number of inflammatory genes. Overall, these data suggest that elevated local E2 levels associate with an epigenetic down-regulation of the estrogen receptors and have a prominent role in CP/CPPS. Investigating E2 levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy. PMID:29731970

Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS.

PubMed

Nesheim, Nils; Ellem, Stuart; Dansranjavin, Temuujin; Hagenkötter, Christina; Berg, Elena; Schambeck, Rupert; Schuppe, Hans-Christian; Pilatz, Adrian; Risbridger, Gail; Weidner, Wolfgang; Wagenlehner, Florian; Schagdarsurengin, Undraga

2018-04-13

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III ( n = 50; median age 39.8, range 23-65) and age-matched controls ( n = 61; median age 36.8, range 20-69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes ( ESR1 and ESR2 ) in leukocytes isolated from blood (systemic regulation) and in somatic cells isolated from ejaculates (local regulation). We found elevated 17β-estradiol (E 2 ) levels in seminal plasma, but not in blood plasma, that was significantly associated with CP/CPPS and impaired urinary tract symptoms. In ejaculated somatic cells of CP/CPPS patients we found that ESR1 and ESR2 were both significantly higher methylated in CpG-promoters and expressionally down-regulated in comparison to controls. Mast cells are reported to contribute to CP/CPPS and are estrogen responsive. Consistent with this, we found that E 2 -treatment of human mast cell lines (HMC-1 and LAD2) resulted in altered cytokine and chemokine expression. Interestingly, in HMC-1 cells, possessing epigenetically inactivated ESR1 and ESR2, E 2 -treatment led to a reduced transcription of a number of inflammatory genes. Overall, these data suggest that elevated local E 2 levels associate with an epigenetic down-regulation of the estrogen receptors and have a prominent role in CP/CPPS. Investigating E 2 levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy.

Whole exome sequence-based association analyses of plasma amyloid-β in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study.

PubMed

Simino, Jeannette; Wang, Zhiying; Bressler, Jan; Chouraki, Vincent; Yang, Qiong; Younkin, Steven G; Seshadri, Sudha; Fornage, Myriam; Boerwinkle, Eric; Mosley, Thomas H

2017-01-01

We performed single-variant and gene-based association analyses of plasma amyloid-β (aβ) concentrations using whole exome sequence from 1,414 African and European Americans. Our goal was to identify genes that influence plasma aβ42 concentrations and aβ42:aβ40 ratios in late middle age (mean = 59 years), old age (mean = 77 years), or change over time (mean = 18 years). Plasma aβ measures were linearly regressed onto age, gender, APOE ε4 carrier status, and time elapsed between visits (fold-changes only) separately by race. Following inverse normal transformation of the residuals, seqMeta was used to conduct race-specific single-variant and gene-based association tests while adjusting for population structure. Linear regression models were fit on autosomal variants with minor allele frequencies (MAF)≥1%. T5 burden and Sequence Kernel Association (SKAT) gene-based tests assessed functional variants with MAF≤5%. Cross-race fixed effects meta-analyses were Bonferroni-corrected for the number of variants or genes tested. Seven genes were associated with aβ in late middle age or change over time; no associations were identified in old age. Single variants in KLKB1 (rs3733402; p = 4.33x10-10) and F12 (rs1801020; p = 3.89x10-8) were significantly associated with midlife aβ42 levels through cross-race meta-analysis; the KLKB1 variant replicated internally using 1,014 additional participants with exome chip. ITPRIP, PLIN2, and TSPAN18 were associated with the midlife aβ42:aβ40 ratio via the T5 test; TSPAN18 was significant via the cross-race meta-analysis, whereas ITPRIP and PLIN2 were European American-specific. NCOA1 and NT5C3B were associated with the midlife aβ42:aβ40 ratio and the fold-change in aβ42, respectively, via SKAT in African Americans. No associations replicated externally (N = 725). We discovered age-dependent genetic effects, established associations between vascular-related genes (KLKB1, F12, PLIN2) and midlife plasma aβ levels, and

Plasma Cell Cheilitis: A Clinicopathological and Immunohistochemical Study of 13 Cases

PubMed Central

Lee, Jin Yong; Kim, Kwang Ho; Hahm, Ji Eun; Ha, Jae Won; Kwon, Won Joo; Kim, Chul Woo

2017-01-01

Background Plasma cell cheilitis is an unusual benign plasma cell proliferative disease of an unknown etiology that typically presents on the lip. Objective The aim of this study was to investigate the clinicopathological characteristics of 13 cases of plasma cell cheilitis. Methods The present study investigated the clinical manifestations, treatment modalities, and outcome of 13 patients diagnosed with plasma cell cheilitis from 2011 to 2016 at Kangdong Sacred Heart Hospital and Hallym University Sacred Heart Hospital. Biopsy specimens of the all cases were evaluated using conventional hematoxylin and eosin staining with kappa and lambda immunoglobulin light chain immunohistochemistry. Results The age of the patients ranged from 39 to 86 years (mean, 64.7 years), with male predominance. Histopathologically, 61.5% and 38.5% of patients showed band-like and pan dermal plasmacytic infiltrates, respectively. Eosinophilic infiltration was noted in 69.2% of patients. All cases showed both kappa and lambda immunoglobulin light chain reactivities, and kappa predominance was confirmed in 9 patients (69.2%). A majority of the patients was treated with local therapy, such as intralesional steroid injection with topical tacrolimus. Among the 13 patients, plasma cell cheilitis completely resolved, partially resolved, and recurred in 3 (23.1%), 5 (38.5%), and 5 patients (38.5%), respectively. Conclusion Plasma cell cheilitis presented as erosive edematous circumscribed patches or plaques affecting mainly the lower lip of elderly male patients. The majority of histopathology cases showed characteristic plasma cell aggregation on the upper dermis that was immunopositive for immunoglobulin light chain, with kappa predominance. PMID:28966508

The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

PubMed Central

Bongmba, Odelia Y. N.; Ma, Xiaojun; Zhu, Xiongwei; Sheikh-Hamad, David; Sun, Yuxiang

2014-01-01

Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS-R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS-R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS-R regulates thermogenesis via both central and peripheral mechanisms. Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS-R may serve as unique anti-obesity agents, combating obesity by activating thermogenesis. PMID:25543537

Myosin Vb Is Associated with Plasma Membrane Recycling Systems

PubMed Central

Lapierre, Lynne A.; Kumar, Ravindra; Hales, Chadwick M.; Navarre, Jennifer; Bhartur, Sheela G.; Burnette, Jason O.; Provance, D. William; Mercer, John A.; Bähler, Martin; Goldenring, James R.

2001-01-01

Myosin Va is associated with discrete vesicle populations in a number of cell types, but little is known of the function of myosin Vb. Yeast two-hybrid screening of a rabbit parietal cell cDNA library with dominant active Rab11a (Rab11aS20V) identified myosin Vb as an interacting protein for Rab11a, a marker for plasma membrane recycling systems. The isolated clone, corresponding to the carboxyl terminal 60 kDa of the myosin Vb tail, interacted with all members of the Rab11 family (Rab11a, Rab11b, and Rab25). GFP-myosin Vb and endogenous myosin Vb immunoreactivity codistributed with Rab11a in HeLa and Madin-Darby canine kidney (MDCK) cells. As with Rab11a in MDCK cells, the myosin Vb immunoreactivity was dispersed with nocodazole treatment and relocated to the apical corners of cells with taxol treatment. A green fluorescent protein (GFP)-myosin Vb tail chimera overexpressed in HeLa cells retarded transferrin recycling and caused accumulation of transferrin and the transferrin receptor in pericentrosomal vesicles. Expression of the myosin Vb tail chimera in polarized MDCK cells stably expressing the polymeric IgA receptor caused accumulation of basolaterally endocytosed polymeric IgA and the polymeric IgA receptor in the pericentrosomal region. The myosin Vb tail had no effects on transferrin trafficking in polarized MDCK cells. The GFP-myosin Va tail did not colocalize with Rab11a and had no effects on recycling system vesicle distribution in either HeLa or MDCK cells. The results indicate myosin Vb is associated with the plasma membrane recycling system in nonpolarized cells and the apical recycling system in polarized cells. The dominant negative effects of the myosin Vb tail chimera indicate that this unconventional myosin is required for transit out of plasma membrane recycling systems. PMID:11408590

Lipid Domains in Intact Fiber-Cell Plasma Membranes Isolated from Cortical and Nuclear Regions of Human Eye Lenses of Donors from Different Age Groups

PubMed Central

Raguz, Marija; Mainali, Laxman; O’Brien, William J.; Subczynski, Witold K.

2015-01-01

The results reported here clearly document changes in the properties and the organization of fiber-cell membrane lipids that occur with age, based on electron paramagnetic resonance (EPR) analysis of lens membranes of clear lenses from donors of age groups from 0 to 20, 21 to 40, and 61 to 80 years. The physical properties, including profiles of the alkyl chain order, fluidity, hydrophobicity, and oxygen transport parameter, were investigated using EPR spin-labeling methods, which also provide an opportunity to discriminate coexisting lipid domains and to evaluate the relative amounts of lipids in these domains. Fiber-cell membranes were found to contain three distinct lipid environments: bulk lipid domain, which appears minimally affected by membrane proteins, and two domains that appear due to the presence of membrane proteins, namely boundary and trapped lipid domains. In nuclear membranes the amount of boundary and trapped phospholipids as well as the amount of cholesterol in trapped lipid domains increased with the donors’ age and was greater than that in cortical membranes. The difference between the amounts of lipids in domains uniquely formed due to the presence of membrane proteins in nuclear and cortical membranes increased with the donors’ age. It was also shown that cholesterol was to a large degree excluded from trapped lipid domains in cortical membranes. It is evident that the rigidity of nuclear membranes was greater than that of cortical membranes for all age groups. The amount of lipids in domains of low oxygen permeability, mainly in trapped lipid domains, were greater in nuclear than cortical membranes and increased with the age of donors. These results indicate that the nuclear fiber cell plasma membranes were less permeable to oxygen than cortical membranes and become less permeable to oxygen with age. In clear lenses, age-related changes in the lens lipid and protein composition and organization appear to occur in ways that increase fiber

Lipid domains in intact fiber-cell plasma membranes isolated from cortical and nuclear regions of human eye lenses of donors from different age groups.

PubMed

Raguz, Marija; Mainali, Laxman; O'Brien, William J; Subczynski, Witold K

2015-03-01

The results reported here clearly document changes in the properties and the organization of fiber-cell membrane lipids that occur with age, based on electron paramagnetic resonance (EPR) analysis of lens membranes of clear lenses from donors of age groups from 0 to 20, 21 to 40, and 61 to 80 years. The physical properties, including profiles of the alkyl chain order, fluidity, hydrophobicity, and oxygen transport parameter, were investigated using EPR spin-labeling methods, which also provide an opportunity to discriminate coexisting lipid domains and to evaluate the relative amounts of lipids in these domains. Fiber-cell membranes were found to contain three distinct lipid environments: bulk lipid domain, which appears minimally affected by membrane proteins, and two domains that appear due to the presence of membrane proteins, namely boundary and trapped lipid domains. In nuclear membranes the amount of boundary and trapped phospholipids as well as the amount of cholesterol in trapped lipid domains increased with the donors' age and was greater than that in cortical membranes. The difference between the amounts of lipids in domains uniquely formed due to the presence of membrane proteins in nuclear and cortical membranes increased with the donors' age. It was also shown that cholesterol was to a large degree excluded from trapped lipid domains in cortical membranes. It is evident that the rigidity of nuclear membranes was greater than that of cortical membranes for all age groups. The amount of lipids in domains of low oxygen permeability, mainly in trapped lipid domains, were greater in nuclear than cortical membranes and increased with the age of donors. These results indicate that the nuclear fiber cell plasma membranes were less permeable to oxygen than cortical membranes and become less permeable to oxygen with age. In clear lenses, age-related changes in the lens lipid and protein composition and organization appear to occur in ways that increase fiber

Nonthermal-plasma-mediated animal cell death

NASA Astrophysics Data System (ADS)

Kim, Wanil; Woo, Kyung-Chul; Kim, Gyoo-Cheon; Kim, Kyong-Tai

2011-01-01

Animal cell death comprising necrosis and apoptosis occurred in a well-regulated manner upon specific stimuli. The physiological meanings and detailed molecular mechanisms of cell death have been continuously investigated over several decades. Necrotic cell death has typical morphological changes, such as cell swelling and cell lysis followed by DNA degradation, whereas apoptosis shows blebbing formation and regular DNA fragmentation. Cell death is usually adopted to terminate cancer cells in vivo. The current strategies against tumour are based on the induction of cell death by adopting various methods, including radiotherapy and chemotherapeutics. Among these, radiotherapy is the most frequently used treatment method, but it still has obvious limitations. Recent studies have suggested that the use of nonthermal air plasma can be a prominent method for inducing cancer cell death. Plasma-irradiated cells showed the loss of genomic integrity, mitochondrial dysfunction, plasma membrane damage, etc. Tumour elimination with plasma irradiation is an emerging concept in cancer therapy and can be accelerated by targeting certain tumour-specific proteins with gold nanoparticles. Here, some recent developments are described so that the mechanisms related to plasma-mediated cell death and its perspectives in cancer treatment can be understood.

Clinically granulomatous cheilitis with plasma cells

PubMed Central

Sarkar, Somenath; Ghosh, Sarmistha; Sengupta, Dipayan

2016-01-01

Plasma cell cheilitis, also known as plasma cell orificial mucositis is a benign inflammatory condition clinically characterized by erythematous plaque on lips that may be ulcerated. Histopathologically it is characterized by dense plasma cell infiltrates in a band-like pattern in dermis, which corresponds to Zoon's plasma cell balanitis. On the other hand, granulomatous cheilitis, as a part of orofacial granulomatosis, manifests as sudden diffuse or nodular swelling involving lip and cheek. Initial swelling is soft to firm, but with recurrent episodes swelling gradually become firm rubbery in consistency. We hereby report a case of cheilitis in a 52-year-old man with diffuse swelling involving lower lip, which clinically resembles granulomatous cheilitis, but histopathological examination showed diffuse infiltrate of plasma cells predominantly in upper and mid-dermis. PMID:27057489

Comparison of EBV DNA viral load in whole blood, plasma, B-cells and B-cell culture supernatant.

PubMed

Ouedraogo, David Eric; Bollore, Karine; Viljoen, Johannes; Foulongne, Vincent; Reynes, Jacques; Cartron, Guillaume; Vendrell, Jean-Pierre; Van de Perre, Philippe; Tuaillon, Edouard

2014-05-01

Epstein-Barr virus (EBV) genome quantitation in whole blood is used widely for therapeutic monitoring of EBV-associated disorders in immunosuppressed individuals and in patients with EBV-associated lymphoma. However, the most appropriate biological material to be used for EBV DNA quantitation remains a subject of debate. This study compare the detection rate and levels of EBV DNA from whole blood, plasma, enriched B-cells, and B-cell short-term culture supernatant using quantitative real-time PCR. Samples were collected from 33 subjects with either HIV infection or B-cell lymphoma. Overall, EBV DNA was detected in 100% of enriched B-cell samples, in 82% of B-cell culture supernatants, in 57% of plasma, and 42% of whole blood samples. A significant correlation for EBV viral load was found between enriched B-cell and B-cell culture supernatant material (ρ = 0.92; P < 0.0001), but no significant correlation existed between EBV DNA levels in whole blood and enriched B-cells (ρ = -0.02; P = 0.89), whole blood and plasma (ρ = 0.24; P = 0.24), or enriched B-cells and plasma (ρ = 0.08; P = 0.77). Testing of enriched B-cells appeared to be the most sensitive method for detection of EBV DNA as well as for exploration of the cellular reservoir. Quantitation of EBV DNA in plasma and B-cell culture supernatant may be of interest to assess EBV reactivation dynamics and response to treatment as well as to decipher EBV host-pathogen interactions in various clinical scenarios. © 2013 Wiley Periodicals, Inc.

PLASMA CELL LEUKEMIA

PubMed Central

de Larrea, Carlos Fernandez; Kyle, Robert A.; Durie, Brian GM; Ludwig, Heinz; Usmani, Saad; Vesole, David H.; Hajek, Roman; Miguel, Jésus San; Sezer, Orhan; Sonneveld, Pieter; Kumar, Shaji K.; Mahindra, Anuj; Comenzo, Ray; Palumbo, Antonio; Mazumber, Amitabha; Anderson, Kenneth C.; Richardson, Paul G.; Badros, Ashraf Z.; Caers, Jo; Cavo, Michele; LeLeu, Xavier; Dimopoulos, Meletios A.; Chim, CS; Schots, Rik; Noeul, Amara; Fantl, Dorotea; Mellqvist, Ulf-Henrik; Landgren, Ola; Chanan-Khan, Asher; Moreau, Philippe; Fonseca, Rafael; Merlini, Giampaolo; Lahuerta, JJ; Bladé, Joan; Orlowski, Robert Z.; Shah, Jatin J.

2014-01-01

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathologic entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10 9/L) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be reexamined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL. PMID:23288300

Do plasma melatonin concentrations decline with age?

NASA Technical Reports Server (NTRS)

Zeitzer, J. M.; Daniels, J. E.; Duffy, J. F.; Klerman, E. B.; Shanahan, T. L.; Dijk, D. J.; Czeisler, C. A.

1999-01-01

PURPOSE: Numerous reports that secretion of the putative sleep-promoting hormone melatonin declines with age have led to suggestions that melatonin replacement therapy be used to treat sleep problems in older patients. We sought to reassess whether the endogenous circadian rhythm of plasma melatonin concentration changes with age in healthy drug-free adults. METHODS: We analyzed the amplitude of plasma melatonin profiles during a constant routine in 34 healthy drug-free older subjects (20 women and 14 men, aged 65 to 81 years) and compared them with 98 healthy drug-free young men (aged 18 to 30 years). RESULTS: We could detect no significant difference between a healthy and drug-free group of older men and women as compared to one of young men in the endogenous circadian amplitude of the plasma melatonin rhythm, as described by mean 24-hour average melatonin concentration (70 pmol/liter vs 73 pmol/liter, P = 0.97), or the duration (9.3 hours vs 9.1 hours, P = 0.43), mean (162 pmol/liter vs 161 pmol/liter, P = 0.63), or integrated area (85,800 pmol x min/liter vs 86,700 pmol x min/liter, P = 0.66) of the nocturnal peak of plasma melatonin. CONCLUSION: These results do not support the hypothesis that reduction of plasma melatonin concentration is a general characteristic of healthy aging. Should melatonin replacement therapy or melatonin supplementation prove to be clinically useful, we recommend that an assessment of endogenous melatonin be carried out before such treatment is used in older patients.

Binge drinking and total alcohol consumption from 16 to 43 years of age are associated with elevated fasting plasma glucose in women: results from the northern Swedish cohort study.

PubMed

Nygren, Karina; Hammarström, Anne; Rolandsson, Olov

2017-06-08

Studies have indicated that moderate alcohol consumption is associated with lower incidence of diabetes in women. However, not only the amount but also the drinking pattern could be of importance when assessing the longitudinal relation between alcohol and glucose. Also, there is a lack of studies on alcohol use beginning in adolescence on adult glucose levels. The aim was to examine the association between total alcohol consumption and binge drinking between ages 16 and 43 and fasting plasma glucose at age 43. Data were retrieved from a 27-year prospective cohort study, the Northern Swedish Cohort. In 1981, all 9th grade students (n = 1083) within a municipality in Sweden were invited to participate. There were re-assessments at ages 18, 21, 30 and 43. This particular study sample consisted of 897 participants (82.8%). Fasting plasma glucose (mmol/L) was measured at a health examination at age 43. Total alcohol consumption (in grams) and binge drinking were calculated from alcohol consumption data obtained from questionnaires. Descriptive analyses showed that men had higher levels of fasting plasma glucose as compared to women. Men also reported higher levels of alcohol consumption and binge drinking behavior. Linear regressions showed that total alcohol consumption in combination with binge drinking between ages 16 and 43 was associated with elevated fasting plasma glucose at age 43 in women (beta = 0.14, p = 0.003) but not in men after adjustment for BMI, hypertension and smoking at age 43. Our findings indicate that reducing binge drinking and alcohol consumption among young and middle-aged women with the highest consumption might be metabolically favorable for their future glucose metabolism.

Plasma glial cell line-derived neurotrophic factor in patients with major depressive disorder: a preliminary study.

PubMed

Lee, Bun-Hee; Hong, Jin-Pyo; Hwang, Jung-A; Na, Kyoung-Sae; Kim, Won-Joong; Trigo, Jose; Kim, Yong-Ku

2016-02-01

Some clinical studies have reported reduced peripheral glial cell line-derived neurotrophic factor (GDNF) level in elderly patients with major depressive disorder (MDD). We verified whether a reduction in plasma GDNF level was associated with MDD. Plasma GDNF level was measured in 23 healthy control subjects and 23 MDD patients before and after 6 weeks of treatment. Plasma GDNF level in MDD patients at baseline did not differ from that in healthy controls. Plasma GDNF in MDD patients did not differ significantly from baseline to the end of treatment. GDNF level was significantly lower in recurrent-episode MDD patients than in first-episode patients before and after treatment. Our findings revealed significantly lower plasma GDNF level in recurrent-episode MDD patients, although plasma GDNF levels in MDD patients and healthy controls did not differ significantly. The discrepancy between our study and previous studies might arise from differences in the recurrence of depression or the ages of the MDD patients.

Increased Levels of Cell-Free miR-517a and Decreased Levels of Cell-Free miR-518b in Maternal Plasma Samples From Placenta Previa Pregnancies at 32 Weeks of Gestation.

PubMed

Hasegawa, Yuri; Miura, Kiyonori; Higashijima, Ai; Abe, Shuhei; Miura, Shoko; Yoshiura, Koh-ichiro; Masuzaki, Hideaki

2015-12-01

The aim of this study was to clarify the association between placenta previa and circulating levels of cell-free pregnancy-associated placenta-specific microRNAs (miRNAs) in maternal plasma. Twenty singleton pregnancies with placenta previa (placenta previa group) and 26 uncomplicated pregnancies (control group) were recruited. Blood sampling was performed at 32 weeks of gestation, and cesarean delivery in all cases of placenta previa was performed at a mean gestational age of 37 weeks. The maternal plasma concentrations of cell-free pregnancy-associated placenta-specific miRNAs (miR-517a and miR-518b) were measured by absolute quantitative real-time reverse transcription-polymerase chain reaction. Plasma concentrations of cell-free miR-517a were significantly higher in the placenta previa group than that in the control group (P = .011), while the plasma concentration of cell-free miR-518b was significantly lower in the placenta previa group than that in the control group (P = .004). Plasma concentrations of cell-free miR-517a in placenta previa were significantly higher in placenta previa with alert bleeding later group than those in placenta previa without alert bleeding group or control group (P = .030 or .047, respectively) and correlated with the volume of hemorrhage at delivery (R and P value: .512 and .025). Plasma concentrations of cell-free miR-517a and miR-518b at 32 weeks of gestation were altered in pregnant women with placenta previa, and the circulating level of cell-free miR-517a in placenta previa may be a predictive marker for the risks of alert bleeding later and massive hemorrhage at delivery. © The Author(s) 2015.

β-cell serotonin production is associated with female sex, old age, and diabetes-free condition.

PubMed

Kim, Yeong Gi; Moon, Joon Ho; Kim, Kyuho; Kim, Hyeongseok; Kim, Juok; Jeong, Ji-Seon; Lee, Junguee; Kang, Shinae; Park, Joon Seong; Kim, Hail

2017-11-25

Serotonin is known to be present in pancreatic β-cells and to play several physiological roles, including insulin secretion, β-cell proliferation, and paracrine inhibition of α-cells. However, the serotonin production of different cell lines and islets has not been compared based on age, sex, and diabetes related conditions. Here, we directly compared the serotonin concentrations in βTC and MIN6 cell lines, as well as in islets from mice using ultra-performance liquid chromatography tandem mass spectrometry. The average serotonin concentration was 5-10 ng/mg protein in the islets of male and non-pregnant female mice. The serotonin level was higher in females than males at 8 weeks, although there was no difference at 1 year. Furthermore, we observed serotonin by immunofluorescence staining in the pancreatic tissues of mice and human. Serotonin was detected by immunofluorescence staining in a portion of β-cells from islets of old female mice, but not of male or young female mice. A similar pattern was observed in human pancreas as well. In humans, serotonin production in β-cells was associated with a diabetes-free condition. Thus, serotonin production in β-cells was associated with old age, female sex, and diabetes-free condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Aging of cell membranes: facts and theories.

PubMed

Zs-Nagy, Imre

2014-01-01

This chapter is intended to outline the main results of a research trend realized by the author during the last 45 years, focused on the main role played by the cell membrane in the aging process. It is a very wide field; therefore, the reader cannot expect in this limited space a detailed description, but will be given a wide, interdisciplinary insight into the main facts and theories regarding cellular aging. The central idea described here is the concept called the membrane hypothesis of aging (MHA). The history, the chemical roots, physicochemical facts, biophysical processes, as well as the obligatory biochemical consequences are all touched in by indicating the most important sources of detailed knowledge for those who are more interested in the basic biology of the aging process. This chapter covers also the available anti-aging interventions on the cell membrane by means of the centrophenoxine treatment based on the MHA. It also briefly interprets the possibilities of a just developing anti-aging method by using the recombinant human growth hormone, essential basis of which is the species specificity, and the general presence of receptors of this hormone in the plasma membrane of all types of cells.

Elevated plasma and urinary concentrations of green tea catechins associated with improved plasma lipid profile in healthy Japanese women.

PubMed

Takechi, Ryusuke; Alfonso, Helman; Hiramatsu, Naoko; Ishisaka, Akari; Tanaka, Akira; Tan, La'Belle; Lee, Andy H

2016-03-01

This study investigated green tea catechins in plasma and urine and chronic disease biomarkers. We hypothesized that plasma and urinary concentration of green tea catechins are associated with cardiovascular disease and diabetes biomarkers. First void urine and fasting plasma samples were collected from 57 generally healthy females aged 38 to 73 years (mean, 52 ± 8 years) recruited in Himeji, Japan. The concentrations of plasma and urinary green tea catechins were determined by liquid chromatography coupled with mass tandem spectrometer. Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, glucose, insulin, glycated hemoglobin, and C-reactive protein in plasma/serum samples were analyzed by a commercial diagnostic laboratory. Statistical associations were assessed using Spearman correlation coefficients. The results showed weak associations between plasma total catechin and triglyceride (r = -0.30) and LDL cholesterol (r = -0.28), whereas plasma (-)-epigallocatechin-3-gallate, (-)-epigallocatechin, (-)-epicatechin-3-gallate, and (-)-epicatechin exhibited weak to moderate associations with triglyceride or LDL cholesterol, but little associations with HDL cholesterol, body fat, and body mass index were evident. Urinary total catechin was weakly associated with triglyceride (r = -0.19) and LDL cholesterol (r = -0.15), whereas urinary (-)-epigallocatechin-3-gallate (r = -0.33), (-)-epigallocatechin (r = -0.23), and (-)-epicatechin-3-gallate (r = -0.33) had weak to moderate correlations with triglyceride and similarly with body fat and body mass index. Both plasma (r = -0.24) and urinary (r = -0.24) total catechin, as well as individual catechins, were weakly associated with glycated hemoglobin. Plasma total and individual catechins were weakly to moderately associated with C-reactive protein, but not the case for urinary catechins. In conclusion, we found weak to moderate associations between plasma and urinary green tea

Age-Related Decline in Primary CD8+ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8+ T Cells.

PubMed

Quinn, Kylie M; Fox, Annette; Harland, Kim L; Russ, Brendan E; Li, Jasmine; Nguyen, Thi H O; Loh, Liyen; Olshanksy, Moshe; Naeem, Haroon; Tsyganov, Kirill; Wiede, Florian; Webster, Rosela; Blyth, Chantelle; Sng, Xavier Y X; Tiganis, Tony; Powell, David; Doherty, Peter C; Turner, Stephen J; Kedzierska, Katherine; La Gruta, Nicole L

2018-06-19

Age-associated decreases in primary CD8 + T cell responses occur, in part, due to direct effects on naive CD8 + T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated "virtual memory" (T VM ) cells, but their contribution to age-related functional decline is unclear. Here, we show that T VM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (T N cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged T VM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

PubMed Central

Akunuru, Shailaja; Geiger, Hartmut

2016-01-01

Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as clonal selection of HSCs upon aging provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and potentially, alleviating aging-associated immune remodeling and myeloid malignancies. PMID:27380967

Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiation in Vitro.

PubMed

Jeffery, Louisa; Fisk, Helena L; Calder, Philip C; Filer, Andrew; Raza, Karim; Buckley, Christopher D; McInnes, Iain; Taylor, Peter C; Fisher, Benjamin A

2017-06-01

To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF-driven Th17 cell differentiation. Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25- T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry. Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (-0.51, p = 0.007 and -0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequencies in vitro . Physiological concentrations of EPA, but not LA, prevented this. EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro . EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity

PubMed Central

Lindqvist, D; Fernström, J; Grudet, C; Ljunggren, L; Träskman-Bendz, L; Ohlsson, L; Westrin, Å

2016-01-01

Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic–pituitary–adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-values<2.98E−12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho=0.49, P<0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression. PMID:27922635

The role of IgG4 (+) plasma cells in the association of Hashimoto's thyroiditis with papillary carcinoma.

PubMed

Taşli, Funda; Ozkök, Güliz; Argon, Asuman; Ersöz, Didem; Yağci, Ayşe; Uslu, Adam; Erkan, Nazif; Salman, Tarik; Vardar, Enver

2014-12-01

Hashimoto's thyroiditis (HT) is considered to be a risk factor for the formation of papillary carcinoma. The association of IgG4-related sclerosing disease with tumor is reported to be as sporadic cases in many organs. In this study, it was intended to re-classify the HT diagnosed cases on the basis of the existence of IgG4 (+) plasma cells; to investigate the clinicopathologic and histopathologic features of the both groups; and in addition, to evaluate the papillary carcinoma prevalence in IgG4 (+) and IgG4 (-) HT cases as well as the prognostic parameters between these groups. Totally 59 cases between the years 2008-2013, 29 of which contain Hashimoto thyroiditis diagnosis in total thyroidectomy materials, and 30 of which contain the diagnosis of HT+papillary carcinoma, were included in the study. The materials were immunohistochemically applied IgG and IgG4; and the cases were classified in two groups as IgG4-positive HT and IgG4-negative HT containing cases, on the basis of IgG4/IgG rate. All histopathologic and clinicopathologic parameters between these two groups, as well as their association with papillary carcinoma were investigated. Thirty eight (64.4%) of total 59 cases were NonIgG4 thyroiditis, and 21 (35.5%) were IgG4 thyroiditis. Tumors were detected in 14 (36.8%) of the NonIgG4 thyroiditis cases, and in 16 (76.1%) of the IgG4 thyroiditis cases. The association of IgG4 thyroiditis with tumor is statistically significant (p < 0.004). Multifocality was found to be at a higher rate in IgG4 thyroiditis cases. Perithyroidal extension was detected in six of the cases with tumor, and five of the six cases were IgG4 thyroiditis cases. The association of IgG4 (+) HT cases with increased papillary carcinoma prevalence is suggestive of that IgG4 (+) plasma cells can play a role in carcinogenesis in papillary carcinomas developed in HTs, without a chronic sclerosing ground. In addition, although the number of cases is limited, the high-association of IgG4

Plasma protein hydroperoxides during aging in humans: correlation with paraoxonase 1 (PON1) arylesterase activity and plasma total thiols.

PubMed

Mehdi, Mohammad Murtaza; Rizvi, Syed Ibrahim

2013-02-01

Oxidative stress is thought to play a major role in the development of several age-dependent diseases. Proteins are major targets for oxidative attack. Protein hydroperoxides are formed by hydroxyl and singlet oxygen attack on protein, forming relatively stable hydroperoxides on histidine, tyrosine and tryptophan residues. This study investigated the levels of plasma protein hydroperoxides and antioxidant potential of plasma during aging in humans. We correlated the protein hydroperoxide formation with plasma antioxidant potential, paraoxonase 1 (PON1) arylesterase activity and plasma total thiols. The protein hydroperoxides and antioxidant potential were measured in plasma of human subjects aged between 20 and 81 years of both genders. Increase in plasma protein hydroperoxides and decrease in plasma antioxidant potential were observed as function of human age. This study provides strong correlation between plasma protein hydroperoxides formation and decrease in plasma antioxidant potential during aging. PON1 arylesterase activity and plasma total thiols levels were also found to show significant correlation with increasing levels of plasma protein hydroperoxides during aging. The plasma protein hydroperoxides provide a reliable marker of long-term redox balance and degree of oxidative stress during aging process. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women.

PubMed

Konstantinova, Svetlana V; Tell, Grethe S; Vollset, Stein Emil; Nygård, Ottar; Bleie, Øyvind; Ueland, Per Magne

2008-05-01

Choline is involved in the synthesis of phospholipids, including blood lipids, and is the immediate precursor of betaine, which serves as a methyl group donor in a reaction converting homocysteine to methionine. Several cardiovascular risk factors are associated with plasma homocysteine, whereas little is known about their relationship to choline and betaine. We examined the relation of plasma choline and betaine to smoking, physical activity, BMI, percent body fat, waist circumference, blood pressure, serum lipids, and glucose in a population-based study of 7074 men and women aged 47-49 and 71-74 y. Overall plasma concentrations (means +/- SD) were 9.9 +/- 2.3 micromol/L for choline and 39.5 +/- 12.5 micromol/L for betaine. Choline and betaine were lower in women than in men and in younger subjects compared with older (P < 0.0001). Multivariate analyses showed that choline was positively associated with serum triglycerides, glucose, BMI, percent body fat, waist circumference (P < 0.0001 for all), and physical activity (P < 0.05) and inversely related to HDL cholesterol (P < 0.05) and smoking (P < 0.0001). Betaine was inversely associated with serum non-HDL cholesterol, triglycerides, BMI, percent body fat, waist circumference, systolic and diastolic blood pressure (P < 0.0001 for all), and smoking (P < 0.05) and positively associated with HDL cholesterol (P < 0.01) and physical activity (P < 0.0001). Thus, an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations. Choline and betaine were associated in opposite directions with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline dehydrogenase pathway.

Red blood cells for transfusion in patients with sepsis: respective roles of unit age and exposure to recipient plasma.

PubMed

Chadebech, Philippe; Bodivit, Gwellaouen; Razazi, Keyvan; de Vassoigne, Christophe; Pellé, Laurence; Burin-des-Roziers, Nicolas; Bocquet, Thibault; Bierling, Philippe; Djoudi, Rachid; Mekontso-Dessap, Armand; Pirenne, France

2017-08-01

Red blood cell (RBC) storage in blood banks is not exempt from cellular injury. Alterations not observed on RBCs freshly isolated from units can rapidly appear in circulation. The transfusion of old blood units, even if this is a controversial issue, could therefore have adverse effects on the recipient. We wanted to determine the respective effects of storage duration and recipient plasma on RBCs for transfusion into patients with severe sepsis. Eleven stored RBC units were sampled at various time points, approximately Days 3 to 8 (referred to as fresh RBCs) and Days 38 to 42 (old RBCs) and tested in coincubation experiments with plasma obtained from 13 patients with severe sepsis and 17 healthy donors as controls. RBCs were tested after 24 or 48 hours at 37°C for the detection of senescence markers (phosphatidylserine exposure, calcium influx, and reactive oxygen species detection and decrease in size) with or without exposure to plasma. We confirmed that a 42-day refrigerated storage of RBCs alone (without any incubation in plasma) had no significant effect on RBCs and no senescence marker detected. By contrast, ex vivo exposure to plasma samples altered both fresh and old RBCs, with a much larger effect for old RBCs, regardless of the plasma used (sepsis vs. control). We show that the main factor affecting the senescence of RBCs for transfusion into patients with severe sepsis is the age of the stored units rather than the clinical status of the recipient. © 2017 AABB.

Prehospital plasma resuscitation associated with improved neurologic outcomes after traumatic brain injury.

PubMed

Hernandez, Matthew C; Thiels, Cornelius A; Aho, Johnathon M; Habermann, Elizabeth B; Zielinski, Martin D; Stubbs, James A; Jenkins, Donald H; Zietlow, Scott P

2017-09-01

Trauma-related hypotension and coagulopathy worsen secondary brain injury in patients with traumatic brain injuries (TBIs). Early damage control resuscitation with blood products may mitigate hypotension and coagulopathy. Preliminary data suggest resuscitation with plasma in large animals improves neurologic function after TBI; however, data in humans are lacking. We retrospectively identified all patients with multiple injuries age >15 years with head injuries undergoing prehospital resuscitation with blood products at a single Level I trauma center from January 2002 to December 2013. Inclusion criteria were prehospital resuscitation with either packed red blood cells (pRBCs) or thawed plasma as sole colloid resuscitation. Patients who died in hospital and those using anticoagulants were excluded. Primary outcomes were Glasgow Outcomes Score Extended (GOSE) and Disability Rating Score (DRS) at dismissal and during follow-up. Of 76 patients meeting inclusion criteria, 53% (n = 40) received prehospital pRBCs and 47% (n = 36) received thawed plasma. Age, gender, injury severity or TBI severity, arrival laboratory values, and number of prehospital units were similar (all p > 0.05). Patients who received thawed plasma had an improved neurologic outcome compared to those receiving pRBCs (median GOSE 7 [7-8] vs. 5.5 [3-7], p < 0.001). Additionally, patients who received thawed plasma had improved functionality compared to pRBCs (median DRS 2 [1-3.5] vs. 9 [3-13], p < 0.001). Calculated GOSE and DRS scores during follow-up, median 6 [5-7] months, demonstrated increased function in those resuscitated with thawed plasma compared to pRBCs by both median GOSE (8 [7-8] vs. 6 [6-7], p < 0.001) and DRS (0 [0-1] vs. 4 [2-8], p < 0.001). In critically injured trauma patients with TBI, early resuscitation with thawed plasma is associated with improved neurologic and functional outcomes at discharge and during follow-up compared to pRBCs alone. These preliminary data support the

Surface wettability of plasma SiOx:H nanocoating-induced endothelial cells' migration and the associated FAK-Rho GTPases signalling pathways

PubMed Central

Shen, Yang; Wang, Guixue; Huang, Xianliang; Zhang, Qin; Wu, Jiang; Tang, Chaojun; Yu, Qingsong; Liu, Xiaoheng

2012-01-01

Vascular endothelial cell (EC) adhesion and migration are essential processes in re-endothelialization of implanted biomaterials. There is no clear relationship and mechanism between EC adhesion and migration behaviour on surfaces with varying wettabilities. As model substrates, plasma SiOx:H nanocoatings with well-controlled surface wettability (with water contact angles in the range of 98.5 ± 2.3° to 26.3 ± 4.0°) were used in this study to investigate the effects of surface wettability on cell adhesion/migration and associated protein expressions in FAK-Rho GTPases signalling pathways. It was found that EC adhesion/migration showed opposite behaviour on the hydrophilic and hydrophobic surfaces (i.e. hydrophobic surfaces promoted EC migration but were anti-adhesions). The number of adherent ECs showed a maximum on hydrophilic surfaces, while cells adhered to hydrophobic surfaces exhibited a tendency for cell migration. The focal adhesion kinase (FAK) inhibitor targeting the Y-397 site of FAK could significantly inhibit cell adhesion/migration, suggesting that EC adhesion and migration on surfaces with different wettabilities involve (p)FAK and its downstream signalling pathways. Western blot results suggested that the FAK-Rho GTPases signalling pathways were correlative to EC migration on hydrophobic plasma SiOx:H surfaces, but uncertain to hydrophilic surfaces. This work demonstrated that surface wettability could induce cellular behaviours that were associated with different cellular signalling events. PMID:21715399

Plasma membrane microorganization of LR73 multidrug-resistant cells revealed by FCS

NASA Astrophysics Data System (ADS)

Winckler, Pascale; Jaffiol, Rodolphe; Cailler, Aurélie; Morjani, Hamid; Jeannesson, Pierre; Deturche, Régis

2011-03-01

Tumoral cells could present a multidrug resistance (MDR) to chemotherapeutic treatments. This drug resistance would be associated to biomechanisms occurring at the plasma membrane level, involving modification of membrane fluidity, drug permeability, presence of microdomains (rafts, caveolae...), and membrane proteins overexpression such as Pglycoprotein. Fluorescence correlation spectroscopy (FCS) is the relevant method to investigate locally the fluidity of biological membranes through the lateral diffusion of a fluorescent membrane probe. Thus, we use FCS to monitor the plasma membrane local organization of LR73 carcinoma cells and three derived multidrug-resistant cancer cells lines. Measurements were conducted at the single cell level, which enabled us to get a detailed overview of the plasma membrane microviscosity distribution of each cell line studied. Moreover, we propose 2D diffusion simulation based on a Monte Carlo model to investigate the membrane organisation in terms of microdomains. This simulation allows us to relate the differences in the fluidity distributions with microorganization changes in plasma membrane of MDR cells.

Follicular B Cells Promote Atherosclerosis via T Cell-Mediated Differentiation Into Plasma Cells and Secreting Pathogenic Immunoglobulin G.

PubMed

Tay, Christopher; Liu, Yu-Han; Kanellakis, Peter; Kallies, Axel; Li, Yi; Cao, Anh; Hosseini, Hamid; Tipping, Peter; Toh, Ban-Hock; Bobik, Alex; Kyaw, Tin

2018-05-01

B cells promote or protect development of atherosclerosis. In this study, we examined the role of MHCII (major histocompatibility II), CD40 (cluster of differentiation 40), and Blimp-1 (B-lymphocyte-induced maturation protein) expression by follicular B (FO B) cells in development of atherosclerosis together with the effects of IgG purified from atherosclerotic mice. Using mixed chimeric Ldlr -/- mice whose B cells are deficient in MHCII or CD40, we demonstrate that these molecules are critical for the proatherogenic actions of FO B cells. During development of atherosclerosis, these deficiencies affected T-B cell interactions, germinal center B cells, plasma cells, and IgG. As FO B cells differentiating into plasma cells require Blimp-1, we also assessed its role in the development of atherosclerosis. Blimp-1-deficient B cells greatly attenuated atherosclerosis and immunoglobulin-including IgG production, preventing IgG accumulation in atherosclerotic lesions; Blimp-1 deletion also attenuated lesion proinflammatory cytokines, apoptotic cell numbers, and necrotic core. To determine the importance of IgG for atherosclerosis, we purified IgG from atherosclerotic mice. Their transfer but not IgG from nonatherosclerotic mice into Ldlr -/- mice whose B cells are Blimp-1-deficient increased atherosclerosis; transfer was associated with IgG accumulating in atherosclerotic lesions, increased lesion inflammatory cytokines, apoptotic cell numbers, and necrotic core size. The mechanism by which FO B cells promote atherosclerosis is highly dependent on their expression of MHCII, CD40, and Blimp-1. FO B cell differentiation into IgG-producing plasma cells also is critical for their proatherogenic actions. Targeting B-T cell interactions and pathogenic IgG may provide novel therapeutic strategies to prevent atherosclerosis and its adverse cardiovascular complications. © 2018 American Heart Association, Inc.

Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell-associated damage in IFNα-driven lupus nephritis.

PubMed

Katewa, Arna; Wang, Yugang; Hackney, Jason A; Huang, Tao; Suto, Eric; Ramamoorthi, Nandhini; Austin, Cary D; Bremer, Meire; Chen, Jacob Zhi; Crawford, James J; Currie, Kevin S; Blomgren, Peter; DeVoss, Jason; DiPaolo, Julie A; Hau, Jonathan; Johnson, Adam; Lesch, Justin; DeForge, Laura E; Lin, Zhonghua; Liimatta, Marya; Lubach, Joseph W; McVay, Sami; Modrusan, Zora; Nguyen, Allen; Poon, Chungkee; Wang, Jianyong; Liu, Lichuan; Lee, Wyne P; Wong, Harvey; Young, Wendy B; Townsend, Michael J; Reif, Karin

2017-04-06

Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens. Selective Btk inhibition ablated plasmablast generation, reduced autoantibodies, and - similar to cyclophosphamide - improved renal pathology in IFNα-accelerated lupus. Employing global transcriptional profiling of spleen and kidney coupled with cross-species human modular repertoire analyses, we identify similarities in the inflammatory process between mice and humans, and we demonstrate that G-744 reduced gene expression signatures essential for splenic B cell terminal differentiation, particularly the secretory pathway, as well as renal transcriptional profiles coupled with myeloid cell-mediated pathology and glomerular plus tubulointerstitial disease in human glomerulonephritis patients. These findings reveal the mechanism through which a selective Btk inhibitor blocks murine autoimmune kidney disease, highlighting pathway activity that may translate to human SLE.

Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.

PubMed

Tanaka, Toshiko; Shen, Jian; Abecasis, Gonçalo R; Kisialiou, Aliaksei; Ordovas, Jose M; Guralnik, Jack M; Singleton, Andrew; Bandinelli, Stefania; Cherubini, Antonio; Arnett, Donna; Tsai, Michael Y; Ferrucci, Luigi

2009-01-01

Polyunsaturated fatty acids (PUFA) have a role in many physiological processes, including energy production, modulation of inflammation, and maintenance of cell membrane integrity. High plasma PUFA concentrations have been shown to have beneficial effects on cardiovascular disease and mortality. To identify genetic contributors of plasma PUFA concentrations, we conducted a genome-wide association study of plasma levels of six omega-3 and omega-6 fatty acids in 1,075 participants in the InCHIANTI study on aging. The strongest evidence for association was observed in a region of chromosome 11 that encodes three fatty acid desaturases (FADS1, FADS2, FADS3). The SNP with the most significant association was rs174537 near FADS1 in the analysis of arachidonic acid (AA; p = 5.95 x 10(-46)). Minor allele homozygotes had lower AA compared to the major allele homozygotes and rs174537 accounted for 18.6% of the additive variance in AA concentrations. This SNP was also associated with levels of eicosadienoic acid (EDA; p = 6.78 x 10(-9)) and eicosapentanoic acid (EPA; p = 1.07 x 10(-14)). Participants carrying the allele associated with higher AA, EDA, and EPA also had higher low-density lipoprotein (LDL-C) and total cholesterol levels. Outside the FADS gene cluster, the strongest region of association mapped to chromosome 6 in the region encoding an elongase of very long fatty acids 2 (ELOVL2). In this region, association was observed with EPA (rs953413; p = 1.1 x 10(-6)). The effects of rs174537 were confirmed in an independent sample of 1,076 subjects participating in the GOLDN study. The ELOVL2 SNP was associated with docosapentanoic and DHA but not with EPA in GOLDN. These findings show that polymorphisms of genes encoding enzymes in the metabolism of PUFA contribute to plasma concentrations of fatty acids.

Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel.

PubMed

Yu, Y; Daly, D M; Adam, I J; Kitsanta, P; Hill, C J; Wild, J; Shorthouse, A; Grundy, D; Jiang, W

2016-10-01

Advanced age is associated with a reduction in clinical visceral pain perception. However, the underlying mechanisms remain largely unknown. Previous studies have suggested that an abnormal interplay between mast cells, enterochromaffin (EC) cells, and afferent nerves contribute to nociception in gastrointestinal disorders. The aim of this study was to investigate how aging affects afferent sensitivity and neuro-immune association in the human bowel. Mechanical and chemical sensitivity of human bowel afferents were examined by ex vivo afferent nerve recordings. Age-related changes in the density of mast cells, EC cells, sensory nerve terminals, and mast cell-nerve micro-anatomical association were investigated by histological and immune staining. Human afferents could be broadly classified into subpopulations displaying mechanical and chemical sensitivity, adaptation, chemo-sensitization, and recruitment. Interestingly human bowel afferent nerve sensitivity was attenuated with age. The density of substance P-immunoreactive (SP-IR) nerve varicosities was also reduced with age. In contrast, the density of ileal and colonic mucosal mast cells was increased with age, as was ileal EC cell number. An increased proportion of mast cells was found in close apposition to SP-IR nerves. Afferent sensitivity in human bowel was reduced with advancing age. Augmentation of mast cells and EC cell numbers and the mast cell-nerve association suggest a compensatory mechanism for sensory neurodegeneration. © 2016 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.

Mouse model of plasma cell mastitis.

PubMed

Yu, Jian-jun; Bao, Shan-lin; Yu, Sheng-lin; Zhang, Da-Qing; Loo, Wings T Y; Chow, Louis W C; Su, Li; Cui, Zhen; Chen, Kai; Ma, Li-Qiong; Zhang, Ning; Yu, Hui; Yang, Yun-Zhen; Dong, Yu; Yip, Adrian Y S; Ng, Elizabeth L Y

2012-09-19

Plasma cell mastitis is distinct from the common form of mastitis and clinically resembles breast carcinoma. The lesion occurs in non-lactating young women, and the incidence rate is rising. Surgical resection is the main treatment, but cannot prevent recurrence of the disease. Disfigurement or removal of breast after the operations can cause marked physical and psychological distress. The etiology of plasma cell mastitis is unclear up till now. It is therefore necessary to investigate further the underlying immunological changes of the disease. The lesions of plasma cell mastitis removed from patients through aseptic operation were mixed with normal saline into homogenate tube machine (homogenate tubes were disinfected and sterilized prior to treatment). The mixture was homogenized at medium speed and grinded in ultrasonic cell disruptor. The homogenate obtained was made into oil emulsion with Freund's adjuvant. Thirty female BALB/c mice (6 weeks after sexual maturity) were divided into five groups A-E: group A was blank control; group B was normal saline control; group C was inoculated with 0.02 ml water-in-oil emulsion; group D was inoculated with 0.04 ml water-in-oil emulsion; group E was complete Freund's adjuvant control. Pathology results showed that mouse mammary gland acinar cells remained integral without any abnormal changes observed in control groups A and B. Experimental groups C and D showed dilation of mouse mammary ductal tissue with a large number of epithelial cells and debris in the lumen, and fibrosis around ducts accompanied by large duct cells, neutrophils, lymphocytes, and especially plasma cell infiltration. Pathological changes were observed in 3 (50%) mice and 5 (83.3%) mice in group C and D respectively. In group E, neutrophil infiltration in mammary gland was observed in 5 mice, but neither infiltration of plasma cells nor other abnormal pathological changes were observed. The lesions of patient with plasma cell mastitis could make the

Effects of Aged Stored Autologous Red Blood Cells on Human Endothelial Function

PubMed Central

Kanias, Tamir; Triulzi, Darrel; Donadee, Chenell; Barge, Suchitra; Badlam, Jessica; Jain, Shilpa; Belanger, Andrea M.; Kim-Shapiro, Daniel B.

2015-01-01

Rationale: A major abnormality that characterizes the red cell “storage lesion” is increased hemolysis and reduced red cell lifespan after infusion. Low levels of intravascular hemolysis after transfusion of aged stored red cells disrupt nitric oxide (NO) bioavailabity, via accelerated NO scavenging reaction with cell-free plasma hemoglobin. The degree of intravascular hemolysis post-transfusion and effects on endothelial-dependent vasodilation responses to acetylcholine have not been fully characterized in humans. Objectives: To evaluate the effects of blood aged to the limits of Food and Drug Administration–approved storage time on the human microcirculation and endothelial function. Methods: Eighteen healthy individuals donated 1 U of leukopheresed red cells, divided and autologously transfused into the forearm brachial artery 5 and 42 days after blood donation. Blood samples were obtained from stored blood bag supernatants and the antecubital vein of the infusion arm. Forearm blood flow measurements were performed using strain-gauge plethysmography during transfusion, followed by testing of endothelium-dependent blood flow with increasing doses of intraarterial acetylcholine. Measurements and Main Results: We demonstrate that aged stored blood has higher levels of arginase-1 and cell-free plasma hemoglobin. Compared with 5-day blood, the transfusion of 42-day packed red cells decreases acetylcholine-dependent forearm blood flows. Intravascular venous levels of arginase-1 and cell-free plasma hemoglobin increase immediately after red cell transfusion, with more significant increases observed after infusion of 42-day-old blood. Conclusions: We demonstrate that the transfusion of blood at the limits of Food and Drug Administration–approved storage has a significant effect on the forearm circulation and impairs endothelial function. Clinical trial registered with www.clinicaltrials.gov (NCT 01137656) PMID:26222884

Interactions of the plasma needle with cells in culture

NASA Astrophysics Data System (ADS)

Stoffels, E.; Broers, J. L. V.; Kunts, S.; Cornelis, R. A. A.; Caubet, V.; Ramaekers, F. C. S.

2002-10-01

A non-thermal atmospheric plasma source (plasma needle) has been developed. This plasma operates at room temperature, low voltages and power levels, so it can be applied for fine treatment of organic material. In this work the impact of the plasma needle on living cells is explored. For this purpose CHO-K1 (Chinese hamster ovary) cells in culture have been plasma-treated and their responses have been recorded by means of propidium iodide staining. Plasma treatment at low to intermediate power levels leads to damage of the DNA in the cell nucleus, which causes cell death. Characteristic features are high precision of plasma action (influenced cells are strictly localized) and induction of cell death without destroying the cell integrity. Possibilities of using plasma treatment for removal of unwanted cells (e.g. cancer cells) will be investigated.

Stages of Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Age-Associated Decline in Dendritic Cell Function and the Impact of Mediterranean Diet Intervention in Elderly Subjects.

PubMed

Clements, Sarah J; Maijo, Monica; Ivory, Kamal; Nicoletti, Claudio; Carding, Simon R

2017-01-01

Aging is accompanied by increased susceptibility to infection and age-associated chronic diseases. It is also associated with reduced vaccine responses, which is often attributed to immunosenescence and the functional decline of the immune system. Immunosenescence is characterized by a chronic, low-grade, inflammatory state termed inflammaging. Habitants of Mediterranean (MED) regions maintain good health into old age; often attributed to MED diets. Adoption of a MED-diet by elderly subjects, in Norfolk (UK), may improve immune responses of these individuals and in particular, dendritic cell (DC) function. A total of 120 elderly subjects (65-79 years old) recruited onto the Nu-AGE study, a multicenter European dietary study specifically addressing the needs of the elderly, across five countries, and were randomized to the control or MED-diet groups, for one year. Blood samples were taken pre- and post-intervention for DC analysis and were compared with each other, and to samples obtained from 45 young (18-40 years old) subjects. MED-diet compliance was assessed using high performance liquid chromatography-with tandem mass spectrometry analysis of urine samples. Immune cell and DC subset numbers and concentrations of secreted proteins were determined by flow cytometric analysis. As expected, reduced myeloid DC numbers were observed in blood samples from elderly subjects compared with young. The elevated secretion of the adipokine, resistin, after ex vivo stimulation of peripheral blood mononuclear cells from elderly subjects, was significantly reduced after MED-diet intervention. This study provides further evidence of numerical and functional effects of aging on DCs. The MED-diet showed potential to impact on the aging immune cells investigated and could provide an economical approach to address problems associated with our aging population.

PLASMA DIHYDROCERAMIDE SPECIES ASSOCIATE WITH WAIST CIRCUMFERENCE IN MEXICAN AMERICAN FAMILIES

PubMed Central

Mamtani, Manju; Meikle, Peter J.; Kulkarni, Hemant; Weir, Jacquelyn M.; Barlow, Christopher K.; Jowett, Jeremy B.; Bellis, Claire; Dyer, Thomas D.; Almasy, Laura; Mahaney, Michael C.; Duggirala, Ravindranath; Comuzzie, Anthony G.; Blangero, John; Curran, Joanne E.

2013-01-01

Objective Waist circumference (WC), the clinical marker of central obesity, is gaining popularity as a screening tool for type 2 diabetes (T2D). While there is epidemiologic evidence favoring the WC-T2D association, its biological substantiation is generally weak. Our objective was to determine the independent association of plasma lipid repertoire with WC. Design and methods We used samples and data from the San Antonio Family Heart Study of 1208 Mexican Americans from 42 extended families. We determined association of plasma lipidomic profiles with the cross-sectionally assessed WC. Plasma lipidomic profiling entailed liquid chromatography with mass spectrometry. Statistical analyses included multivariable polygenic regression models and bivariate trait analyses using the SOLAR software. Results After adjusting for age and sex interactions, body mass index, homeostasis model of assessment – insulin resistance, total cholesterol, triglycerides, high density lipoproteins and use of lipid lowering drugs, dihydroceramides as a class were associated with WC. Dihydroceramide species 18:0, 20:0, 22:0 and 24:1 were significantly associated and genetically correlated with WC. Two sphingomyelin species (31:1 and 41:1) were also associated with WC. Conclusions Plasma dihydroceramide levels independently associate with WC. Thus, high resolution plasma lipidomic studies can provide further credence to the biological underpinnings of the association of WC with T2D. PMID:23929697

Cellular and epigenetic drivers of stem cell ageing.

PubMed

Ermolaeva, Maria; Neri, Francesco; Ori, Alessandro; Rudolph, K Lenhard

2018-06-01

Adult tissue stem cells have a pivotal role in tissue maintenance and regeneration throughout the lifespan of multicellular organisms. Loss of tissue homeostasis during post-reproductive lifespan is caused, at least in part, by a decline in stem cell function and is associated with an increased incidence of diseases. Hallmarks of ageing include the accumulation of molecular damage, failure of quality control systems, metabolic changes and alterations in epigenome stability. In this Review, we discuss recent evidence in support of a novel concept whereby cell-intrinsic damage that accumulates during ageing and cell-extrinsic changes in ageing stem cell niches and the blood result in modifications of the stem cell epigenome. These cumulative epigenetic alterations in stem cells might be the cause of the deregulation of developmental pathways seen during ageing. In turn, they could confer a selective advantage to mutant and epigenetically drifted stem cells with altered self-renewal and functions, which contribute to the development of ageing-associated organ dysfunction and disease.

X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency.

PubMed

Wilson, Sam J; Tsao, Edward H; Webb, Benjamin L J; Ye, Hongtao; Dalton-Griffin, Lucy; Tsantoulas, Christoforos; Gale, Catherine V; Du, Ming-Qing; Whitehouse, Adrian; Kellam, Paul

2007-12-01

Reactivation of lytic replication from viral latency is a defining property of all herpesviruses. Despite this, the authentic physiological cues for the latent-lytic switch are unclear. Such cues should ensure that viral lytic replication occurs under physiological conditions, predominantly in sites which facilitate transmission to permissive uninfected cells and new susceptible hosts. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the B-cell neoplasm primary effusion lymphoma (PEL), in which the virus remains latent. We have previously shown that PEL cells have the gene expression profile and immunophenotype of cycling preplasma cells (plasmablasts). Here, we show that the highly active spliced isoform of plasma cell transcription factor X box binding protein 1 (XBP-1s) is a lytic switch for KSHV. XBP-1s is normally absent in PEL, but the induction of endoplasmic reticulum stress leads to XBP-1s generation, plasma cell-like differentiation, and lytic reactivation of KSHV. XBP-1s binds to and activates the KSHV immediate-early gene ORF50 and synergizes with the ORF50 gene product RTA to induce a full lytic cycle. These data suggest that KSHV remains latent until B-cell terminal differentiation into plasma cells, the transcriptional environment of which provides the physiological "lytic switch" through XBP-1s. This links B-cell terminal differentiation to KSHV lytic reactivation.

Plasma n-6 Fatty Acid Levels Are Associated With CD4 Cell Counts, Hospitalization, and Mortality in HIV-Infected Patients.

PubMed

Kabagambe, Edmond K; Ezeamama, Amara E; Guwatudde, David; Campos, Hannia; Fawzi, Wafaie

2016-12-15

Fatty acids, including n-6 series, modulate immune function, but their effect on CD4 cell counts, death, or hospitalization in HIV-infected patients on antiretroviral therapy is unknown. In a randomized trial for effects of multivitamins in HIV-infected patients in Uganda, we used gas chromatography to measure plasma n-6 fatty acids at baseline; determined CD4 counts at baseline, 3, 6, 12, and 18 months; and recorded hospitalization or death events. The associations of fatty acids with CD4 counts and events were analyzed using repeated-measures analysis of variance and Cox regression, respectively. Among 297 patients with fatty acids measurements, 16 patients died and 69 were hospitalized within 18 months. Except for linoleic acid, n-6 fatty acids levels were positively associated with CD4 counts at baseline but not during follow-up. In models that included all 5 major n-6 fatty acids, age; sex; body mass index; anemia status; use of antiretroviral therapy, multivitamin supplements, and alcohol; and the risk of death or hospitalization decreased significantly with an increase in linoleic acid and gamma-linolenic acid levels, whereas associations for dihomo-gamma-linolenic acid, arachidonic acid, and aolrenic acid were null. The hazard ratios (95% confidence intervals) per 1 SD increase in linoleic acid and gamma-linolenic acid were 0.73 (0.56-0.94) and 0.51 (0.36-0.72), respectively. Gamma-linolenic acid remained significant (hazard ratio = 0.51; 95% confidence interval: 0.35 to 0.68) after further adjustment for other plasma fatty acids. Lower levels of gamma-linolenic acid are associated with lower CD4 counts and an increased risk of death or hospitalization. These results suggest a potential for using n-6 fatty acids to improve outcomes from antiretroviral therapy.

Development of plasma-on-chip: Plasma treatment for individual cells cultured in media

NASA Astrophysics Data System (ADS)

Kumagai, Shinya; Chang, Chun-Yao; Jeong, Jonghyeon; Kobayashi, Mime; Shimizu, Tetsuji; Sasaki, Minoru

2016-01-01

A device consisting of Si microwells and microplasma sources has been fabricated for plasma treatment of individual cells cultured in media. We named the device plasma-on-chip. The microwells have through-holes at the bottom where gas-liquid interfaces form when they are filled with media containing biological samples. The microplasma sources, which supply reactive species, are located on the back of each microwell. Through the gas-liquid interface, the reactive species are supplied to the cells. Chlorella cells were used to demonstrate the feasibility of the device and after three minutes of plasma treatment, the fluorescence intensity of Chlorella cells appeared to be decreased. Optical emission spectroscopy identified O and OH radicals in the plasma, which can affect the cells. In the analysis of biological samples such as human cells or tissues, this device raises the possibility of revealing the mechanisms of plasma medicine in more detail.

Elevated visfatin/pre-B-cell colony-enhancing factor plasma concentration in ischemic stroke.

PubMed

Lu, Li-Fen; Yang, Sheng-Shan; Wang, Chao-Ping; Hung, Wei-Chin; Yu, Teng-Hung; Chiu, Cheng-An; Chung, Fu-Mei; Shin, Shyi-Jang; Lee, Yau-Jiunn

2009-01-01

Visfatin/pre-B-cell colony-enhancing factor is a cytokine that is expressed as a protein in several tissues (e.g., liver, skeletal muscle, immune cells), including adipose tissue, and is reported to stimulate inflammatory cytokine expressions and promote vascular smooth cell maturation. Visfatin may act as a proinflammatory cytokine and be involved in the process of atherosclerosis. In this study, we investigated whether plasma visfatin levels were altered in patients with ischemic stroke. Plasma visfatin concentrations were measured through enzyme immunoassays in patients with ischemic stroke and in control subjects without stroke. The mean plasma concentration of visfatin in the 120 patients with ischemic stroke was significantly higher than that of the 120 control subjects without stroke (51.5 +/- 48.4 v 23.0 +/- 23.9 ng/mL, P < .001). Multiple logistic regression analysis confirmed plasma visfatin to be an independent factor associated with ischemic stroke. Increasing concentrations of visfatin were independently and significantly associated with a higher risk of ischemic stroke when concentrations were analyzed as both a quartile and a continuous variable. The multiple logistic regression analysis-adjusted odds ratios and 95% confidence intervals for ischemic stroke in the second, third, and fourth quartiles were 2.3 (0.7-7.7), 6.9 (2.2-23.3), and 20.1 (4.9-97.7), respectively. Plasma visfatin concentration was positively associated with high-sensitivity C-reactive protein levels and negatively associated with low-density lipoprotein cholesterol. Our results indicate that higher visfatin levels are associated with ischemic stroke in the Chinese population.

High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort.

PubMed

Paul, Ligi; Jacques, Paul F; Aviv, Abraham; Vasan, Ramachandran S; D'Agostino, Ralph B; Levy, Daniel; Selhub, Jacob

2015-03-01

Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length. We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n = 1,044, females = 52.1 %, mean age 59 years) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay. There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that in the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P < 0.01). There was a linear decrease in leukocyte telomere length with higher plasma folate concentrations in the upper four quintiles of plasma folate (P for trend = 0.001). Multivitamin use was associated with shorter telomeres in this cohort (P = 0.015). High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity.

Variety of RNAs in Peripheral Blood Cells, Plasma, and Plasma Fractions

PubMed Central

Kuligina, Elena V.; Bariakin, Dmitry N.; Kozlov, Vadim V.; Richter, Vladimir A.; Semenov, Dmitry V.

2017-01-01

Human peripheral blood contains RNA in cells and in extracellular membrane vesicles, microvesicles and exosomes, as well as in cell-free ribonucleoproteins. Circulating mRNAs and noncoding RNAs, being internalized, possess the ability to modulate vital processes in recipient cells. In this study, with SOLiD sequencing technology, we performed identification, classification, and quantification of RNAs from blood fractions: cells, plasma, plasma vesicles pelleted at 16,000g and 160,000g, and vesicle-depleted plasma supernatant of healthy donors and non-small cell lung cancer (NSCLC) patients. It was determined that 16,000g blood plasma vesicles were enriched with cell-free mitochondria and with a set of mitochondrial RNAs. The variable RNA set of blood plasma 160,000g pellets reflected the prominent contribution of U1, U5, and U6 small nuclear RNAs' fragments and at the same time was characterized by a remarkable depletion of small nucleolar RNAs. Besides microRNAs, the variety of fragments of mRNAs and snoRNAs dominated in the set of circulating RNAs differentially expressed in blood fractions of NSCLC patients. Taken together, our data emphasize that not only extracellular microRNAs but also circulating fragments of messenger and small nuclear/nucleolar RNAs represent prominent classes of circulating regulatory ncRNAs as well as promising circulating biomarkers for the development of disease diagnostic approaches. PMID:28127559

β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats.

PubMed

Téllez, Noèlia; Vilaseca, Marina; Martí, Yasmina; Pla, Arturo; Montanya, Eduard

2016-09-01

Limitations in β-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated β-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px + V) and gastrin administration (Px + G). Pancreatic remnants were analyzed 3 and 14 days after surgery. β-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, β-cell mass did not change after Px or after gastrin treatment in middle-aged rats. β-Cell replication and individual β-cell size were similarly increased after Px in young and middle-aged animals, and β-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet β-cells of middle-aged rats and further increased after Px. The percentage of chromogranin A+/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory β-cell hyperplasia and hypertrophy was retained in middle-aged rats, but β-cell dedifferentiation and impaired duct cell plasticity limited β-cell regeneration. Copyright © 2016 the American Physiological Society.

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age.

PubMed

Rinaldi, Stefano; Pallikkuth, Suresh; George, Varghese K; de Armas, Lesley R; Pahwa, Rajendra; Sanchez, Celeste M; Pallin, Maria Fernanda; Pan, Li; Cotugno, Nicola; Dickinson, Gordon; Rodriguez, Allan; Fischl, Margaret; Alcaide, Maria; Gonzalez, Louis; Palma, Paolo; Pahwa, Savita

2017-04-01

Combination antiretroviral therapies (cART)can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative "healthy controls" (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (<40 yrs), middle-aged (40-59yrs) or old ( > 60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction.

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age

PubMed Central

George, Varghese K.; de Armas, Lesley R.; Pahwa, Rajendra; Sanchez, Celeste M.; Pallin, Maria Fernanda; Pan, Li; Cotugno, Nicola; Dickinson, Gordon; Rodriguez, Allan; Fischl, Margaret; Alcaide, Maria; Gonzalez, Louis; Palma, Paolo; Pahwa, Savita

2017-01-01

Combination antiretroviral therapies (cART) can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative “healthy controls” (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (<40 yrs), middle-aged (40-59yrs) or old (≥60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction. PMID:28448963

Regulation of Stem Cell Aging by Metabolism and Epigenetics.

PubMed

Ren, Ruotong; Ocampo, Alejandro; Liu, Guang-Hui; Izpisua Belmonte, Juan Carlos

2017-09-05

Stem cell aging and exhaustion are considered important drivers of organismal aging. Age-associated declines in stem cell function are characterized by metabolic and epigenetic changes. Understanding the mechanisms underlying these changes will likely reveal novel therapeutic targets for ameliorating age-associated phenotypes and for prolonging human healthspan. Recent studies have shown that metabolism plays an important role in regulating epigenetic modifications and that this regulation dramatically affects the aging process. This review focuses on current knowledge regarding the mechanisms of stem cell aging, and the links between cellular metabolism and epigenetic regulation. In addition, we discuss how these interactions sense and respond to environmental stress in order to maintain stem cell homeostasis, and how environmental stimuli regulate stem cell function. Additionally, we highlight recent advances in the development of therapeutic strategies to rejuvenate dysfunctional aged stem cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Plasma Cell Depletion Attenuates Hypertension in an Experimental Model of Autoimmune Disease.

PubMed

Taylor, Erin B; Barati, Michelle T; Powell, David W; Turbeville, Hannah R; Ryan, Michael J

2018-04-01

Numerous studies show a direct relation between circulating autoantibodies, characteristic of systemic autoimmune disorders, and primary hypertension in humans. Whether these autoantibodies mechanistically contribute to the development of hypertension remains unclear. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by aberrant immunoglobulin production, notably pathogenic autoantibodies, and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Because plasma cells produce the majority of serum immunoglobulins and are the primary source of autoantibodies in SLE, we hypothesized that plasma cell depletion using the proteasome inhibitor bortezomib would lower autoantibody production and attenuate hypertension. Thirty-week-old female SLE (NZBWF1) and control (NZW [New Zealand White]) mice were injected IV with vehicle (0.9% saline) or bortezomib (0.75 mg/kg) twice weekly for 4 weeks. Bortezomib treatment significantly lowered the percentage of bone marrow plasma cells in SLE mice. Total plasma IgG and anti-dsDNA IgG levels were higher in SLE mice compared with control mice but were lowered by bortezomib treatment. Mean arterial pressure (mm Hg) measured in conscious mice by carotid artery catheter was higher in SLE mice than in control mice, but mean arterial pressure was significantly lower in bortezomib-treated SLE mice. Bortezomib also attenuated renal injury, as assessed by albuminuria and glomerulosclerosis, and reduced glomerular immunoglobulin deposition and B and T lymphocytes infiltration into the kidneys. Taken together, these data show that the production of autoantibodies by plasma cells mechanistically contributes to autoimmune-associated hypertension and suggests a potential role for patients with primary hypertension who have increased circulating immunoglobulins. © 2018 American Heart Association, Inc.

Young endothelial cells revive aging blood.

PubMed

Chang, Vivian Y; Termini, Christina M; Chute, John P

2017-11-01

The hematopoietic system declines with age, resulting in decreased hematopoietic stem cell (HSC) self-renewal capacity, myeloid skewing, and immune cell depletion. Aging of the hematopoietic system is associated with an increased incidence of myeloid malignancies and a decline in adaptive immunity. Therefore, strategies to rejuvenate the hematopoietic system have important clinical implications. In this issue of the JCI, Poulos and colleagues demonstrate that infusions of bone marrow (BM) endothelial cells (ECs) from young mice promoted HSC self-renewal and restored immune cell content in aged mice. Additionally, delivery of young BM ECs along with HSCs following total body irradiation improved HSC engraftment and enhanced survival. These results suggest an important role for BM endothelial cells (ECs) in regulating hematopoietic aging and support further research to identify the rejuvenating factors elaborated by BM ECs that restore HSC function and the immune repertoire in aged mice.

Plasma cell treatment device Plasma-on-Chip: Monitoring plasma-generated reactive species in microwells

PubMed Central

Oh, Jun-Seok; Kojima, Shinya; Sasaki, Minoru; Hatta, Akimitsu; Kumagai, Shinya

2017-01-01

We have developed a plasma cell treatment device called Plasma-on-Chip that enables the real-time monitoring of a single cell culture during plasma treatment. The device consists of three parts: 1) microwells for cell culture, 2) a microplasma device for generating reactive oxygen and nitrogen species (RONS) for use in cell treatment, and 3) through-holes (microchannels) that connect each microwell with the microplasma region for RONS delivery. Here, we analysed the delivery of the RONS to the liquid culture medium stored in the microwells. We developed a simple experimental set-up using a microdevice and applied in situ ultraviolet absorption spectroscopy with high sensitivity for detecting RONS in liquid. The plasma-generated RONS were delivered into the liquid culture medium via the through-holes fabricated into the microdevice. The RONS concentrations were on the order of 10–100 μM depending on the size of the through-holes. In contrast, we found that the amount of dissolved oxygen was almost constant. To investigate the process of RONS generation, we numerically analysed the gas flow in the through-holes. We suggest that the circulating gas flow in the through-holes promotes the interaction between the plasma (ionised gas) and the liquid, resulting in enhanced RONS concentrations. PMID:28176800

Quantitative analysis of cell-free Epstein-Barr virus DNA in the plasma of patients with peripheral T-cell and NK-cell lymphomas and peripheral T-cell proliferative diseases.

PubMed

Suwiwat, Supaporn; Pradutkanchana, Jintana; Ishida, Takafumi; Mitarnun, Winyou

2007-12-01

The level of circulating EBV DNA is a prognostic marker in patients with some EBV-associated malignant diseases. To investigate the presence and nature of Epstein-Barr virus (EBV) DNA in the plasma and to evaluate the correlation of plasma concentrations of EBV DNA with the EBV genomic status in peripheral blood T-cells and neoplastic cells and with the clinical outcome of patients with peripheral T-cell and NK-cell lymphomas (PTCL) and peripheral T-cell proliferative diseases (PTPD). EBV DNA in the plasma of 45 patients and 45 controls was measured using real-time PCR. The presence of the EBV genome in the isolated peripheral blood lymphocytes (CD3+ and CD3- cells) was analysed by PCR. Detection of EBV-encoded early RNA (EBER) in corresponding tumor tissues was carried out using in situ hybridization. DNase I digestion was applied to plasma samples to detect naked EBV DNA. Cell-free EBV DNA was detected in 32/38 (84%) of PTCL patients and 5/7 (71%) of PTPD patients, but not in the controls. Patients with EBV genome in peripheral blood CD3+ cells and EBV genome (EBER) in the tumor cells, compared to those without these findings, had significantly higher plasma EBV DNA levels. The majority of circulating EBV DNA molecules was naked form. The plasma EBV DNA levels were not related to survival. The concentration of EBV DNA in the plasma was not a prognostic marker in PTCL and PTPD patients.

Evaluation of IgG4+ Plasma Cell Infiltration in Patients with Systemic Plasmacytosis and Other Plasma Cell-infiltrating Skin Diseases.

PubMed

Takeoka, Shintaro; Kamata, Masahiro; Hau, Carren Sy; Tateishi, Mihoko; Fukaya, Saki; Hayashi, Kotaro; Fukuyasu, Atsuko; Tanaka, Takamitsu; Ishikawa, Takeko; Ohnishi, Takamitsu; Sasajima, Yuko; Watanabe, Shinichi; Tada, Yayoi

2018-04-27

Systemic plasmacytosis is a rare skin disorder characterized by marked infiltration of plasma cells in the dermis. IgG4-related disease is pathologically characterized by lymphoplasmacytic infiltration rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, accompanied by elevated levels of serum IgG4. Reports of cases of systemic plasmacytosis with abundant infiltration of IgG4+ plasma cells has led to discussion about the relationship between systemic plasmacytosis and IgG4-related disease. This study examined IgG4+/IgG+ plasma cell ratios in 4 patients with systemic plasmacytosis and 12 patients with other skin diseases that show marked infiltration of plasma cells. Furthermore, we examined whether these cases met one of the pathological diagnostic criteria for IgG4-related disease (i.e. IgG4+/IgG plasma cells ratio of over 40%). Only one out of 4 patients with systemic plasmacytosis met the criterion. These results suggest that systemic plasmacytosis and IgG4-related disease are distinct diseases.

The genetic network controlling plasma cell differentiation.

PubMed

Nutt, Stephen L; Taubenheim, Nadine; Hasbold, Jhagvaral; Corcoran, Lynn M; Hodgkin, Philip D

2011-10-01

Upon activation by antigen, mature B cells undergo immunoglobulin class switch recombination and differentiate into antibody-secreting plasma cells, the endpoint of the B cell developmental lineage. Careful quantitation of these processes, which are stochastic, independent and strongly linked to the division history of the cell, has revealed that populations of B cells behave in a highly predictable manner. Considerable progress has also been made in the last few years in understanding the gene regulatory network that controls the B cell to plasma cell transition. The mutually exclusive transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors, those that maintain the B cell program, including Pax5, Bach2 and Bcl6, and those that promote and facilitate plasma cell differentiation, notably Irf4, Blimp1 and Xbp1. In this review, we discuss progress in the definition of both the transcriptional and cellular events occurring during late B cell differentiation, as integrating these two approaches is crucial to defining a regulatory network that faithfully reflects the stochastic features and complexity of the humoral immune response. 2011 Elsevier Ltd. All rights reserved.

Declining lymphoid progenitor fitness promotes aging-associated leukemogenesis.

PubMed

Henry, Curtis J; Marusyk, Andriy; Zaberezhnyy, Vadym; Adane, Biniam; DeGregori, James

2010-12-14

Aging is associated with the functional decline of cells, tissues, and organs. At the same time, age is the single most important prognostic factor in the development of most human cancers, including chronic myelogenous and acute lymphoblastic leukemias initiated by Bcr-Abl oncogenic translocations. Prevailing paradigms attribute the association between aging and cancers to the accumulation of oncogenic mutations over time, because the accrual of oncogenic events is thought to be the rate-limiting step in initiation and progression of cancers. Conversely, aging-associated functional decline caused by both cell-autonomous and non-cell-autonomous mechanisms is likely to reduce the fitness of stem and progenitor cell populations. This reduction in fitness should be conducive for increased selection of oncogenic mutations that can at least partially alleviate fitness defects, thereby promoting the initiation of cancers. We tested this hypothesis using mouse hematopoietic models. Our studies indicate that the dramatic decline in the fitness of aged B-lymphopoiesis coincides with altered receptor-associated kinase signaling. We further show that Bcr-Abl provides a much greater competitive advantage to old B-lymphoid progenitors compared with young progenitors, coinciding with restored kinase signaling pathways, and that this enhanced competitive advantage translates into increased promotion of Bcr-Abl-driven leukemias. Moreover, impairing IL-7-mediated signaling is sufficient to promote selection for Bcr-Abl-expressing B progenitors. These studies support an unappreciated causative link between aging and cancer: increased selection of oncogenic mutations as a result of age-dependent alterations of the fitness landscape.

Aging increases cell-to-cell transcriptional variability upon immune stimulation.

PubMed

Martinez-Jimenez, Celia Pilar; Eling, Nils; Chen, Hung-Chang; Vallejos, Catalina A; Kolodziejczyk, Aleksandra A; Connor, Frances; Stojic, Lovorka; Rayner, Timothy F; Stubbington, Michael J T; Teichmann, Sarah A; de la Roche, Maike; Marioni, John C; Odom, Duncan T

2017-03-31

Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4 + T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues. Copyright © 2017, American Association for the Advancement of Science.

Lower plasma choline levels are associated with sleepiness symptoms.

PubMed

Pak, Victoria M; Dai, Feng; Keenan, Brendan T; Gooneratne, Nalaka S; Pack, Allan I

2018-04-01

Sleepiness and cardiovascular disease share common molecular pathways; thus, metabolic risk factors for sleepiness may also predict cardiovascular disease risk. Daytime sleepiness predicts mortality and cardiovascular disease, although the mechanism is unidentified. This study explored the associations between subjective sleepiness and metabolite concentrations in human blood plasma within the oxidative and inflammatory pathways, in order to identify mechanisms that may contribute to sleepiness and cardiovascular disease risk. An exploratory case-control sample of 36 subjects, categorized based on the Epworth Sleepiness Scale (ESS) questionnaire as sleepy (ESS ≥ 10) or non-sleepy (ESS < 10), was recruited among subjects undergoing an overnight sleep study for suspected sleep apnea at the University of Pennsylvania Sleep Center. The average age was 42.4 ± 10.5 years, the mean body mass index (BMI) was 40.0 ± 9.36 kg/m 2 , median Apnea Hypopnea Index (AHI) was 8.2 (IQR: 2.5-26.5), and 52% were male. Fasting morning blood plasma samples were collected after an overnight sleep study. Biomarkers were explored in subjects with sleepiness versus those without using the multiple linear regression adjusting for age, BMI, smoking, Apnea Hypopnea Index (sleep apnea severity), study cohort, and hypertension. The level of choline is significantly lower (P = 0.003) in sleepy subjects (N = 18; mean plasma choline concentration of 8.19 ± 2.62 μmol/L) compared with non-sleepy subjects (N = 18; mean plasma choline concentration of 9.14 ± 2.25 μmol/L). Other markers with suggestive differences (P < 0.1) include isovalerylcarnitine, Alpha-Amino apidipic acid, Spingosine 1 Phosphate, Aspartic Acid, Propionylcarnitine, and Ceramides (fatty acids; C14-C16 and C-18). This pilot study is the first to show that lower levels of plasma choline metabolites are associated with sleepiness. Further exploration of choline and other noted metabolites and their

Plasma serpinB1 is related to insulin sensitivity but not pancreatic β-Cell function in non-diabetic adults.

PubMed

Glicksman, Michael; Asthana, Asha; Abel, Brent S; Walter, Mary F; Skarulis, Monica C; Muniyappa, Ranganath

2017-03-01

Pancreatic β -cell dysfunction because of reduced β -cell mass and function is a primary determinant in the progression of diabetes. Increase in β -cell mass and compensatory hyperinsulinaemia is frequently associated with insulin-resistant states. Although the humoral factors mediating this compensatory response are unknown, serpinB1, a protease inhibitor, has recently been proposed to be one such factor. In this study, we examine the relationships between plasma serpinB1, insulin sensitivity, and pancreatic β -cell function in non-diabetic individuals. 117 subjects (women, n  = 50, men, n  = 67; age= 37.6 ± 10.8; BMI=31.1 ± 7.7 kg/m 2 ) underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) at the NIH Clinical Research Center. Acute insulin response (AIR) and insulin sensitivity index (SI) were obtained from the FSIVGTT with MINMOD analysis. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated from fasting insulin and glucose values. Plasma serpinB1 levels were measured using an ELISA assay. Simple linear correlation analyses were performed to evaluate the relationship between serpinB1 and measures of insulin sensitivity and β -cell function. Circulating serpinB1 levels were unrelated to age, sex, race, BMI, or percent body fat. SI but not AIR significantly correlated with circulating serpinB1 levels ( r  = 0.23, P  < 0.05). QUICKI tended to positively correlate with serpinB1 ( r  = 0.16, P  = 0.09). Circulating serpinB1 is directly associated with insulin sensitivity but not β -cell function in non-diabetic adults. Whether this modest association plays a role in insulin sensitivity in humans remains to be clarified. Published [2017]. This article is a U.S. Government work and is in the public domain in the USA.

Aging of hematopoietic stem cells: DNA damage and mutations?

PubMed

Moehrle, Bettina M; Geiger, Hartmut

2016-10-01

Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Anti-cancer efficacy of nonthermal plasma dissolved in a liquid, liquid plasma in heterogeneous cancer cells

NASA Astrophysics Data System (ADS)

Nguyen, Ngoc Hoan; Park, Hyung Jun; Yang, Sang Sik; Choi, Kyeong Sook; Lee, Jong-Soo

2016-07-01

The therapeutic potential of nonthermal plasma for cancer treatment has been reported recently. The heterogeneity of cancer cells need to be addressed to design effective anticancer treatments. Here, we show that treatment with nonthermal atmospheric-pressure plasma dissolved in a liquid (liquid plasma) induces oxidative stress in heterogeneous populations of cancer cells and ultimately kills these cells via apoptosis, regardless of genetic status, e.g., mutations in p53 and other DNA-damage-response genes. We found that liquid plasma markedly increased the concentration of intracellular and mitochondrial reactive oxygen species (ROS), reflecting an influx from the extracellular milieu. Liquid plasma contributed to mitochondrial accumulation of ROS and depolarization of mitochondrial membrane potential with consequent cell death. Healthy normal cells, however, were hardly affected by the liquid-plasma treatment. The antioxidant N-acetylcysteine blocked liquid-plasma-induced cell death. A knockdown of CuZn-superoxide dismutase or Mn-SOD enhanced the plasma-induced cell death, whereas expression of exogenous CuZn-SOD, Mn-SOD, or catalase blocked the cell death. These results suggest that the mitochondrial dysfunction mediated by ROS production is a key contributor to liquid-plasma-induced apoptotic cell death, regardless of genetic variation. Thus, liquid plasma may have clinical applications, e.g., the development of therapeutic strategies and prevention of disease progression despite tumor heterogeneity.

Low-calorie cranberry juice supplementation reduces plasma oxidized LDL and cell adhesion molecule concentrations in men.

PubMed

Ruel, Guillaume; Pomerleau, Sonia; Couture, Patrick; Lemieux, Simone; Lamarche, Benoît; Couillard, Charles

2008-02-01

Elevated circulating concentrations of oxidized LDL (OxLDL) and cell adhesion molecules are considered to be relevant markers of oxidative stress and endothelial activation which are implicated in the development of CVD. On the other hand, it has been suggested that dietary flavonoid consumption may be cardioprotective through possible favourable impacts on LDL particle oxidation and endothelial activation. The present study was undertaken to determine the effect of the daily consumption of low-calorie cranberry juice cocktail on plasma OxLDL, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin concentrations in men. Thirty men (mean age 51 (sd 10) years) were recruited and asked to consume increasing daily doses of cranberry juice cocktail (125, 250 and 500 ml/d) over three successive periods of 4 weeks. Plasma OxLDL and adhesion molecule concentrations were measured by ELISA before and after each phase. We noted a significant decrease in plasma OxLDL concentrations following the intervention (P < 0.0001). We also found that plasma ICAM-1 (P < 0.0001) and VCAM-1 (P < 0.05) concentrations decreased significantly during the course of the study. In summary, the present results show that daily cranberry juice cocktail consumption is associated with decreases in plasma OxLDL, ICAM-1 and VCAM-1 concentrations in men.

Treatment Options for Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Treatment Option Overview (Plasma Cell Neoplasms Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Closed inductively coupled plasma cell

DOEpatents

Manning, Thomas J.; Palmer, Byron A.; Hof, Douglas E.

1990-01-01

A closed inductively coupled plasma cell generates a relatively high power, low noise plasma for use in spectroscopic studies. A variety of gases can be selected to form the plasma to minimize spectroscopic interference and to provide a electron density and temperature range for the sample to be analyzed. Grounded conductors are placed at the tube ends and axially displaced from the inductive coil, whereby the resulting electromagnetic field acts to elongate the plasma in the tube. Sample materials can be injected in the plasma to be excited for spectroscopy.

Closed inductively coupled plasma cell

DOEpatents

Manning, T.J.; Palmer, B.A.; Hof, D.E.

1990-11-06

A closed inductively coupled plasma cell generates a relatively high power, low noise plasma for use in spectroscopic studies is disclosed. A variety of gases can be selected to form the plasma to minimize spectroscopic interference and to provide a electron density and temperature range for the sample to be analyzed. Grounded conductors are placed at the tube ends and axially displaced from the inductive coil, whereby the resulting electromagnetic field acts to elongate the plasma in the tube. Sample materials can be injected in the plasma to be excited for spectroscopy. 1 fig.

Association Between Plasma Level of Galectin-9 and Survival of Patients With Drug-Induced Acute Liver Failure.

PubMed

Rosen, Hugo R; Biggins, Scott W; Niki, Toshiro; Gralla, Jane; Hillman, Holly; Hirashima, Mitsuomi; Schilsky, Michael; Lee, William M

2016-04-01

Fewer than 50% of patients with acute liver failure (ALF) recover spontaneously, and ALF has high mortality without liver transplantation. Kupffer cells have been reported to mediate liver inflammation during drug-induced injury. Galectin-9 is produced by Kupffer cells and has diverse roles in regulating immunity. We investigated whether plasma levels of galectin-9 are associated with outcomes of patients with ALF. We analyzed plasma samples (collected at time of hospital admission) and clinical data from 149 patients included in the Acute Liver Failure Study Group from July 2006 through November 2010 (110 had acetaminophen-induced hepatotoxicity and 39 had nonacetaminophen drug-induced liver injury). We compared data with those from all patients enrolled in the study (from July 1, 2006 through October 30, 2013), and from healthy individuals of similar ages with no evidence of liver disease (control subjects). Plasma levels of galectin-9 were measured using a polyclonal antibody and colorimetric assay. Patients with ALF had statistically higher plasma levels of galectin-9 than control subjects, but levels did not differ significantly between patients with acetaminophen-induced liver injury and drug-induced liver injury. A level of galectin-9 above 690 pg/mL was associated with a statistically significant increase in risk for mortality or liver transplantation caused by ALF. Competing risk analyses associated level of galectin-9 with transplant-free survival, independently of Model For End-Stage Liver Disease score or systemic inflammatory response syndrome. A one-time measurement of plasma galectin-9 level can be used to assign patients with ALF to high-, intermediate-, and low-risk groups. The combination of galectin-9 level and Model For End-Stage Liver Disease score was more closely associated with patient outcome than either value alone. These data might be used to determine patient prognoses and prioritize patients for liver transplantation. Clinical

Enhanced adherence of mouse fibroblast and vascular cells to plasma modified polyethylene.

PubMed

Reznickova, Alena; Novotna, Zdenka; Kolska, Zdenka; Kasalkova, Nikola Slepickova; Rimpelova, Silvie; Svorcik, Vaclav

2015-01-01

Since the last decade, tissue engineering has shown a sensational promise in providing more viable alternatives to surgical procedures for harvested tissues, implants and prostheses. Biomedical polymers, such as low-density polyethylene (LDPE), high-density polyethylene (HDPE) and ultra-high molecular weight polyethylene (UHMWPE), were activated by Ar plasma discharge. Degradation of polymer chains was examined by determination of the thickness of ablated layer. The amount of an ablated polymer layer was measured by gravimetry. Contact angle, measured by goniometry, was studied as a function of plasma exposure and post-exposure aging times. Chemical structure of modified polymers was characterized by angle resolved X-ray photoelectron spectroscopy. Surface chemistry and polarity of the samples were investigated by electrokinetic analysis. Changes in surface morphology were followed using atomic force microscopy. Cytocompatibility of plasma activated polyethylene foils was studied using two distinct model cell lines; VSMCs (vascular smooth muscle cells) as a model for vascular graft testing and connective tissue cells L929 (mouse fibroblasts) approved for standardized material cytotoxicity testing. Specifically, the cell number, morphology, and metabolic activity of the adhered and proliferated cells on the polyethylene matrices were studied in vitro. It was found that the plasma treatment caused ablation of the polymers, resulting in dramatic changes in their surface morphology and roughness. ARXPS and electrokinetic measurements revealed oxidation of the polymer surface. It was found that plasma activation has a positive effect on the adhesion and proliferation of VSMCs and L929 cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Low plasma tryptophan is associated with olfactory function in healthy elderly community dwellers in Japan.

PubMed

Adachi, Yusuke; Shimodaira, Yoshiki; Nakamura, Hidehiro; Imaizumi, Akira; Mori, Maiko; Kageyama, Yoko; Noguchi, Yasushi; Seki, Asuka; Okabe, Yuki; Miyake, Yuko; Ono, Kaori; Kumagai, Shu

2017-10-16

Decreased circulating tryptophan (Trp) levels are frequently observed in elderly patients with neurodegenerative disease including Alzheimer's disease. Trp may serve as a potential biomarker for monitoring disease risk in elderly people. We aimed to investigate the association between low plasma Trp levels and olfactory function, which is known to predict age-related diseases including dementia in elderly people. A total of 144 healthy elderly Japanese community (≥ 65 years old) dwellers from the Health, Aging and Nutritional Improvement study (HANI study) were the subjects of our analysis. Low Trp levels were classified using the lower limit values of the reference interval according to a previous report. Olfactory function was assessed using a card-type test called Open Essence, which includes 12 odour items that are familiar to Japanese people. The elderly subjects with low circulating Trp levels were compared to a control group with normal plasma Trp levels. We conducted the analyses using 144 people aged 65 years or older (mean age 73.7 ± 5.5 years; 36.1% men). The subjects showed normal serum albumin levels (4.4 ± 0.2 g/dL) and no daily living disabilities. Low plasma Trp levels (low Trp group) were found in 11.1% of the study population. The low Trp group showed a significantly lower correct-answer rate for the items india ink, perfume, curry and sweaty smelling socks than control group (P < 0.05). There was also a significant association between low Trp levels and low olfactory ability, after adjusting for age and sex. Lower plasma Trp levels were associated with a decrease in olfactory function in functionally competent older individuals. Because olfactory dysfunction predicts age-related diseases, low plasma Trp levels may represent a clinical sign of disease risk in elderly people.

Plasma needle: treatment of living cells and tissues

NASA Astrophysics Data System (ADS)

Stoffels, Eva

2003-10-01

Non-thermal plasmas are capable of refined treatment of heat sensitive surfaces. Recently, many non-thermal sources working under atmospheric pressure have been constructed. Their main applications are various surface treatments: cleaning, etching, changing the wettability/adhesion, and bacterial decontamination. A new research at the Eindhoven University of Technology focuses on in vivo treatment by means of a novel non-thermal plasma source (the plasma needle). At present, a fundamental study has been undertaken to identify all possible responses of living objects exposed to the plasma. Plasma treatment does not lead to cell death (necrosis), which is a cause of inflammation. On the contrary, we observe various sophisticated reactions of mammalian cells, e.g. cell detachment (loss of cell contact) and programmed cell death (apoptosis). Moreover, under certain conditions the plasma is capable of killing bacteria, while eukaryotic cells remain unharmed. These findings may result in development of new techniques, like bacterial sterilization of infected (living) tissues or removal of cells without inflammatory response, and on a longer time scale to new methods in the health care. Possible applications include treatment of skin ailments, aiding wound healing and sterilization of dental cavities.

Mitotic Dysfunction Associated with Aging Hallmarks.

PubMed

Macedo, Joana Catarina; Vaz, Sara; Logarinho, Elsa

2017-01-01

Aging is a biological process characterized by the progressive deterioration of physiological functions known to be the main risk factor for chronic diseases and declining health. There has been an emerging connection between aging and aneuploidy, an aberrant number of chromosomes, even though the molecular mechanisms behind age-associated aneuploidy remain largely unknown. In recent years, several genetic pathways and biochemical processes controlling the rate of aging have been identified and proposed as aging hallmarks. Primary hallmarks that cause the accumulation of cellular damage include genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis (López-Otín et al., Cell 153:1194-1217, 2013). Here we review the provocative link between these aging hallmarks and the loss of chromosome segregation fidelity during cell division, which could support the correlation between aging and aneuploidy seen over the past decades. Secondly, we review the systemic impacts of aneuploidy in cell physiology and emphasize how these include some of the primary hallmarks of aging. Based on the evidence, we propose a mutual causality between aging and aneuploidy, and suggest modulation of mitotic fidelity as a potential means to ameliorate healthy lifespan.

Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage.

PubMed

Uzer, Gunes; Fuchs, Robyn K; Rubin, Janet; Thompson, William R

2016-06-01

Numerous factors including chemical, hormonal, spatial, and physical cues determine stem cell fate. While the regulation of stem cell differentiation by soluble factors is well-characterized, the role of mechanical force in the determination of lineage fate is just beginning to be understood. Investigation of the role of force on cell function has largely focused on "outside-in" signaling, initiated at the plasma membrane. When interfaced with the extracellular matrix, the cell uses integral membrane proteins, such as those found in focal adhesion complexes to translate force into biochemical signals. Akin to these outside-in connections, the internal cytoskeleton is physically linked to the nucleus, via proteins that span the nuclear membrane. Although structurally and biochemically distinct, these two forms of mechanical coupling influence stem cell lineage fate and, when disrupted, often lead to disease. Here we provide an overview of how mechanical coupling occurs at the plasma and nuclear membranes. We also discuss the role of force on stem cell differentiation, with focus on the biochemical signals generated at the cell membrane and the nucleus, and how those signals influence various diseases. While the interaction of stem cells with their physical environment and how they respond to force is complex, an understanding of the mechanical regulation of these cells is critical in the design of novel therapeutics to combat diseases associated with aging, cancer, and osteoporosis. Stem Cells 2016;34:1455-1463. © 2016 AlphaMed Press.

Short communication: Plasma levels of vitamin D in HIV patients initiating antiretroviral therapy do not predict immune restoration disease associated with Mycobacterium tuberculosis.

PubMed

Price, Patricia; Haddow, Lewis J; Affandi, Jacquita; Agarwal, Upasna; Easterbrook, Philippa J; Elliott, Julian; French, Martyn; Kumar, Manoj; Moosa, Mahomed-Yunus S; Oliver, Benjamin; Singh, Sarman; Sola, Marcelo; Saphonn, Vonthanak; Vun, Mean Chhi

2012-10-01

Immune restoration disease associated with Mycobacterium tuberculosis (TB IRD) is clinically important among HIV patients commencing antiretroviral therapy in countries where tuberculosis is endemic. Vitamin D affects dendritic cell and T cell function and the antimicrobial activity of monocytes. Plasma levels of vitamin D and polymorphisms in the vitamin D receptor may affect tuberculosis, and HIV infection associates with vitamin D deficiency. Here we assess whether plasma vitamin D levels may predict TB IRD. Samples were available from prospective studies of TB IRD in Cambodia (26 cases), India (19 cases), and South Africa (29 cases). IRD cases and controls from each site were similar in age and baseline CD4(+) T cell count. Plasma samples were assessed using 25(OH) vitamin D immunoassay plates. DNA samples were available from a subset of patients and were genotyped for the VDR FokI (F/f) [C/T, rs10735810] SNP. When data from each cohort were pooled to assess ethnic/geographic differences, 25(OH)D levels were higher in Cambodian than Indian or South African patients (p<0.0001) and higher in South African than Indian patients (p<0.0001). TB IRD was not associated with differences in levels of 25(OH)D in any cohort (p=0.36-0.82), irrespective of the patients' prior TB diagnoses/treatment. Carriage of the minor allele of VDR FokI (F/f) was marginally associated with TB IRD in Indian patients (p=0.06) with no association in Cambodians. Neither plasma levels of vitamin D nor the vitamin D allele will usefully predict TB IRD in diverse populations from TB endemic regions.

BK virus (BKV) plasma dynamics in patients with BKV-associated hemorrhagic cystitis following allogeneic stem cell transplantation.

PubMed

Drew, R J; Walsh, A; Ní Laoi, B; Conneally, E; Crowley, B

2013-06-01

The use of real-time polymerase chain reaction testing in the investigation of BK virus (BKV)-associated disease has been widely studied in renal transplant recipients; however, far less research has been done in this area with respect to the plasma BK viral load dynamics of BKV hemorrhagic cystitis (BKV-HC) in hematopoietic stem cell transplant recipients. The aim of this study was to examine the BK viral load dynamics in plasma samples collected from patients post transplant who had laboratory-confirmed BKV-HC. Patients who developed BK viremia were compared with patients who did not develop viremia, and a statistical comparison of risk factors for viremia was performed. Seventeen patients were included in this study. Urine samples from the day of BKV diagnosis were available in 13 of the 17 cases. In total, 154 archived plasma samples from around the time of the BKV-HC event were also included in the study from these 17 patients. The median time from transplantation to the onset of detectable viremia was 68 days. The median viral load in the 13 urine samples was 1.8 × 10(8) copies/mL, which was significantly higher than the median viral load in the 38 positive plasma samples of 6.6 × 10(2) copies/mL (Mann-Whitney test, U = 16, P < 0.001). The lymphocyte count on the day of the positive BKV test was significantly lower in patients with BKV viremia than in patients with no viremia (P = 0.02) and also the white cell and platelet counts were lower on the day of the first positive BKV test. Although there is not inter-patient consistency as regards correlation between urinary BK viral loads and severity of clinical BKV-HC, in individual patients the decline in viral load in plasma did correlate with clinical recovery. © 2013 John Wiley & Sons A/S.

Plasma carotenoids and vitamin C concentrations and risk of urothelial cell carcinoma in the European Prospective Investigation into Cancer and Nutrition.

PubMed

Ros, Martine M; Bueno-de-Mesquita, H Bas; Kampman, Ellen; Aben, Katja K H; Büchner, Frederike L; Jansen, Eugene H J M; van Gils, Carla H; Egevad, Lars; Overvad, Kim; Tjønneland, Anne; Roswall, Nina; Boutron-Ruault, Marie Christine; Kvaskoff, Marina; Perquier, Florence; Kaaks, Rudolf; Chang-Claude, Jenny; Weikert, Steffen; Boeing, Heiner; Trichopoulou, Antonia; Lagiou, Pagona; Dilis, Vardis; Palli, Domenico; Pala, Valeria; Sacerdote, Carlotta; Tumino, Rosario; Panico, Salvatore; Peeters, Petra H M; Gram, Inger T; Skeie, Guri; Huerta, José María; Barricarte, Aurelio; Quirós, José Ramón; Sánchez, María José; Buckland, Genevieve; Larrañaga, Nerea; Ehrnström, Roy; Wallström, Peter; Ljungberg, Börje; Hallmans, Göran; Key, Timothy J; Allen, Naomi E; Khaw, Kay-Tee; Wareham, Nick; Brennan, Paul; Riboli, Elio; Kiemeney, Lambertus A

2012-10-01

Published associations between dietary carotenoids and vitamin C and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. We investigated the association between plasma carotenoids and vitamin C and risk of urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 856 patients with newly diagnosed UCC were matched with 856 cohort members by sex, age at baseline, study center, date and time of blood collection, and fasting status. Plasma carotenoids (α- and β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin) were measured by using reverse-phase HPLC, and plasma vitamin C was measured by using a colorimetric assay. Incidence rate ratios (IRRs) were estimated by using conditional logistic regression with adjustment for smoking status, duration, and intensity. UCC risk decreased with higher concentrations of the sum of plasma carotenoids (IRR for the highest compared with the lowest quartile: 0.64; 95% CI: 0.44, 0.93; P-trend = 0.04). Plasma β-carotene was inversely associated with aggressive UCC (IRR: 0.51; 95% CI: 0.30, 0.88; P-trend = 0.02). Plasma lutein was inversely associated with risk of nonaggressive UCC (IRR: 0.56; 95% CI: 0.32, 0.98; P-trend = 0.05). No association was observed between plasma vitamin C and risk of UCC. Although residual confounding by smoking or other factors cannot be excluded, higher concentrations of plasma carotenoids may reduce risk of UCC, in particular aggressive UCC. Plasma lutein may reduce risk of nonaggressive UCC.

Incompatible type A plasma transfusion in patients requiring massive transfusion protocol: Outcomes of an Eastern Association for the Surgery of Trauma multicenter study.

PubMed

Stevens, W Tait; Morse, Bryan C; Bernard, Andrew; Davenport, Daniel L; Sams, Valerie G; Goodman, Michael D; Dumire, Russell; Carrick, Matthew M; McCarthy, Patrick; Stubbs, James R; Pritts, Timothy A; Dente, Christopher J; Luo-Owen, Xian; Gregory, Jason A; Turay, David; Gomaa, Dina; Quispe, Juan C; Fitzgerald, Caitlin A; Haddad, Nadeem N; Choudhry, Asad; Quesada, Jose F; Zielinski, Martin D

2017-07-01

With a relative shortage of type AB plasma, many centers have converted to type A plasma for resuscitation of patients whose blood type is unknown. The goal of this study is to determine outcomes for trauma patients who received incompatible plasma transfusions as part of a massive transfusion protocol (MTP). As part of an Eastern Association for the Surgery of Trauma multi-institutional trial, registry and blood bank data were collected from eight trauma centers for trauma patients (age, ≥ 15 years) receiving emergency release plasma transfusions as part of MTPs from January 2012 to August 2016. Incompatible type A plasma was defined as transfusion to patient blood type B or type AB. Of the 1,536 patients identified, 92% received compatible plasma transfusions and 8% received incompatible type A plasma. Patient characteristics were similar except for greater penetrating injuries (48% vs 36%; p = 0.01) in the incompatible group. In the incompatible group, patients were transfused more plasma units at 4 hours (median, 9 vs. 5; p < 0.001) and overall for stay (11 vs. 9; p = 0.03). No hemolytic transfusion reactions were reported. Two transfusion-related acute lung injury events were reported in the compatible group. Between incompatible and compatible groups, there was no difference in the rates of acute respiratory distress syndrome (6% vs. 8%; p = 0.589), thromboembolic events (9% vs. 7%; p = 0.464), sepsis (6% vs. 8%; p = 0.589), or acute renal failure (8% vs. 8%, p = 0.860). Mortality at 6 (17% vs. 15%, p = 0.775) and 24 hours (25% vs. 23%, p = 0.544) and at 28 days or discharge (38% vs. 35%, p = 0.486) were similar between groups. Multivariate regression demonstrated that Injury Severity Score, older age and more red blood cell transfusion at 4 hours were independently associated with death at 28 days or discharge; Injury Severity Score and more red blood cell transfusion at 4 hours were predictors for morbidity. Incompatible transfusion was not an independent

Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome.

PubMed

Sidhu, Vishaldeep K; Huang, Bill X; Desai, Abhishek; Kevala, Karl; Kim, Hee-Yong

2016-05-01

Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane proteins supporting synaptic integrity and neurotransmission were downregulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an important role of DHA in synaptic function. In this study, we demonstrate aging-induced synaptic proteome changes and DHA-dependent mitigation of such changes using mass spectrometry-based protein quantitation combined with western blot or messenger RNA analysis. We found significant reduction of 15 synaptic plasma membrane proteins in aging brains including fodrin-α, synaptopodin, postsynaptic density protein 95, synaptic vesicle glycoprotein 2B, synaptosomal-associated protein 25, synaptosomal-associated protein-α, N-methyl-D-aspartate receptor subunit epsilon-2 precursor, AMPA2, AP2, VGluT1, munc18-1, dynamin-1, vesicle-associated membrane protein 2, rab3A, and EAAT1, most of which are involved in synaptic transmission. Notably, the first 9 proteins were further reduced when brain DHA was depleted by diet, indicating that DHA plays an important role in sustaining these synaptic proteins downregulated during aging. Reduction of 2 of these proteins was reversed by raising the brain DHA level by supplementing aged animals with an omega-3 fatty acid sufficient diet for 2 months. The recognition memory compromised in DHA-depleted animals was also improved. Our results suggest a potential role of DHA in alleviating aging-associated cognitive decline by offsetting the loss of neurotransmission-regulating synaptic proteins involved in synaptic function. Published by Elsevier Inc.

Dietary intake of advanced glycation endproducts is associated with higher levels of advanced glycation endproducts in plasma and urine: The CODAM study.

PubMed

Scheijen, Jean L J M; Hanssen, Nordin M J; van Greevenbroek, Marleen M; Van der Kallen, Carla J; Feskens, Edith J M; Stehouwer, Coen D A; Schalkwijk, Casper G

2018-06-01

Advanced glycation endproducts (AGEs) are formed by the reaction between reducing sugars and proteins. AGEs in the body have been associated with several age-related diseases. High-heat treated and most processed foods are rich in AGEs. The aim of our study was to investigate whether dietary AGEs, are associated with plasma and urinary AGE levels. In 450 participants of the Cohort on Diabetes and Atherosclerosis Maastricht study (CODAM study) we measured plasma and urine concentrations of the AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) using UPLC-MS/MS. We also estimated dietary intake of CML, CEL and MG-H1 with the use of a dietary AGE database and a food frequency questionnaire (FFQ). We used linear regression to investigate the association between standardized dietary AGE intake and standardized plasma or urinary AGE levels, after adjustment for age, sex, glucose metabolism status, waist circumference, kidney function, energy- and macro-nutrient intake, smoking status, physical activity, alcohol intake, LDL-cholesterol and markers of oxidative stress. We found that higher intake of dietary CML, CEL and MG-H1 was associated with significantly higher levels of free plasma and urinary CML, CEL and MG-H1 (βCML = 0.253 (95% CI 0.086; 0.415), βCEL = 0.194 (95% CI 0.040; 0.339), βMG-H1 = 0.223 (95% CI 0.069; 0.373) for plasma and βCML = 0.223 (95% CI 0.049; 0.393), βCEL = 0.180 (95% CI 0.019; 0.332), βMG-H1 = 0.196 (95% CI 0.037; 0.349) for urine, respectively). In addition, we observed non-significant associations of dietary AGEs with their corresponding protein bound plasma AGEs. We demonstrate that higher intake of dietary AGEs is associated with higher levels of AGEs in plasma and urine. Our findings may have important implications for those who ingest a diet rich in AGEs. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and

Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational patterns.

PubMed

Cifola, Ingrid; Lionetti, Marta; Pinatel, Eva; Todoerti, Katia; Mangano, Eleonora; Pietrelli, Alessandro; Fabris, Sonia; Mosca, Laura; Simeon, Vittorio; Petrucci, Maria Teresa; Morabito, Fortunato; Offidani, Massimo; Di Raimondo, Francesco; Falcone, Antonietta; Caravita, Tommaso; Battaglia, Cristina; De Bellis, Gianluca; Palumbo, Antonio; Musto, Pellegrino; Neri, Antonino

2015-07-10

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell dyscrasia and may represent a valid model for high-risk multiple myeloma (MM). To provide novel information concerning the mutational profile of this disease, we performed the whole-exome sequencing of a prospective series of 12 pPCL cases included in a Phase II multicenter clinical trial and previously characterized at clinical and molecular levels. We identified 1, 928 coding somatic non-silent variants on 1, 643 genes, with a mean of 166 variants per sample, and only few variants and genes recurrent in two or more samples. An excess of C > T transitions and the presence of two main mutational signatures (related to APOBEC over-activity and aging) occurring in different translocation groups were observed. We identified 14 candidate cancer driver genes, mainly involved in cell-matrix adhesion, cell cycle, genome stability, RNA metabolism and protein folding. Furthermore, integration of mutation data with copy number alteration profiles evidenced biallelically disrupted genes with potential tumor suppressor functions. Globally, cadherin/Wnt signaling, extracellular matrix and cell cycle checkpoint resulted the most affected functional pathways. Sequencing results were finally combined with gene expression data to better elucidate the biological relevance of mutated genes. This study represents the first whole-exome sequencing screen of pPCL and evidenced a remarkable genetic heterogeneity of mutational patterns. This may provide a contribution to the comprehension of the pathogenetic mechanisms associated with this aggressive form of PC dyscrasia and potentially with high-risk MM.

Increased plasma selenium is associated with better outcomes in children with systemic inflammation.

PubMed

Leite, Heitor Pons; Nogueira, Paulo Cesar Koch; Iglesias, Simone Brasil de Oliveira; de Oliveira, Susyane Vieira; Sarni, Roseli Oselka Saccardo

2015-03-01

The aim of this study was to assess the effects of changes in plasma selenium on the outcome of critically ill children. Plasma selenium was prospectively measured in 99 children with acute systemic inflammation. The exposure variables were selenium level on admission and on day 5 of stay in the intensive care unit (ICU) and the difference in selenium concentrations between day 5 post-admission and the ICU admission (delta selenium). Selenium was given only as part of enteral diets. Age, malnutrition, red cell glutathione peroxidase-1 activity, serum C-reactive protein, Pediatric Index of Mortality 2, and Pediatric Logistic Organ Dysfunction scores were analyzed as covariates. The outcome variables were ventilator-free days, ICU-free days, and 28-d mortality. Plasma selenium concentrations increased from admission (median 23.4 μg/L, interquartile range 12.0-30.8) to day 5 (median 25.1 μg/L, interquartile range 16.0-39.0; P = 0.018). After adjustment for confounding factors, a delta selenium increase of 10 μg/L was associated with reductions in ventilator days (1.3 d; 95% confidence interval [CI], 0.2-2.3; P = 0.017) and ICU days (1.4 d; 95% CI, 0.5-2.3; P < 0.01). Delta selenium >0 was associated with decreased 28-d mortality on a univariate model (odds ratio, 0.67; 95% CI, 0.46-0.97; P = 0.036). The mean daily selenium intake (6.82 μg; range 0-48.66 μg) was correlated with the increase in selenium concentrations on day 5. An increase in plasma selenium is independently associated with shorter times of ventilation and ICU stay in children with systemic inflammation. These findings raise the hypothesis that selenium supplementation could be beneficial in children with critical illnesses. Copyright © 2015 Elsevier Inc. All rights reserved.

Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study.

PubMed

Imai, C M; Halldorsson, T I; Aspelund, T; Eiriksdottir, G; Launer, L J; Thorsdottir, I; Harris, T B; Gudnason, V; Brouwer, I A; Gunnarsdottir, I

2018-01-01

Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up.

Gluten Intake Is Positively Associated with Plasma α2-Macroglobulin in Young Adults.

PubMed

Jamnik, Joseph; García-Bailo, Bibiana; Borchers, Christoph H; El-Sohemy, Ahmed

2015-06-01

Gluten-free foods have increased in popularity over the past decade and are now being consumed by individuals without celiac disease. However, the physiologic effects of gluten intake in individuals without celiac disease remain unknown. High-abundance plasma proteins involved in inflammation, endothelial function, and other physiologic pathways may represent potential biomarkers of biological effects of gluten intake. The objective was to examine the association between gluten intake and plasma proteomic biomarkers in a population of adults without clinically diagnosed celiac disease. Subjects (n = 1095) were participants of the Toronto Nutrigenomics and Health Study, a cross-sectional examination of young adults aged 20-29 y. Dietary gluten intake was estimated by using a 1-mo, 196-item semiquantitative food-frequency questionnaire. The concentrations of 54 plasma proteins were measured simultaneously by liquid chromatography/multiple-reaction monitoring mass spectrometry. The association between gluten intake and each proteomic biomarker was examined by using general linear models. Analyses were then conducted in individuals who do not have the human leukocyte antigen (HLA)-DQ2 or DQ8 risk variants required for the development of celiac disease to determine whether any associations observed could have been due to undiagnosed cases of celiac disease. Increased gluten intake was associated with increased concentrations of plasma α2-macroglobulin (P = 0.01), a marker of inflammation and cytokine release. The association remained after adjusting for age, sex, BMI, ethnicity, physical activity, energy intake, fiber intake, and hormonal contraceptive use among women. This relation was not modified by HLA risk variants. Gluten consumption is associated with increased plasma α2-macroglobulin in young adults, which appears to be independent of celiac disease, suggesting possible effects of gluten on inflammation. © 2015 American Society for Nutrition.

Systemic Age-Associated DNA Hypermethylation of ELOVL2 Gene: In Vivo and In Vitro Evidences of a Cell Replication Process.

PubMed

Bacalini, Maria Giulia; Deelen, Joris; Pirazzini, Chiara; De Cecco, Marco; Giuliani, Cristina; Lanzarini, Catia; Ravaioli, Francesco; Marasco, Elena; van Heemst, Diana; Suchiman, H Eka D; Slieker, Roderick; Giampieri, Enrico; Recchioni, Rina; Mercheselli, Fiorella; Salvioli, Stefano; Vitale, Giovanni; Olivieri, Fabiola; Spijkerman, Annemieke M W; Dollé, Martijn E T; Sedivy, John M; Castellani, Gastone; Franceschi, Claudio; Slagboom, Pieternella E; Garagnani, Paolo

2017-08-01

Epigenetic remodeling is one of the major features of the aging process. We recently demonstrated that DNA methylation of ELOVL2 and FHL2 CpG islands is highly correlated with age in whole blood. Here we investigated several aspects of age-associated hypermethylation of ELOVL2 and FHL2. We showed that ELOVL2 methylation is significantly different in primary dermal fibroblast cultures from donors of different ages. Using epigenomic data from public resources, we demonstrated that most of the tissues show ELOVL2 and FHL2 hypermethylation with age. Interestingly, ELOVL2 hypermethylation was not found in tissues with very low replication rate. We demonstrated that ELOVL2 hypermethylation is associated with in vitro cell replication rather than with senescence. We confirmed intra-individual hypermethylation of ELOVL2 and FHL2 in longitudinally assessed participants from the Doetinchem Cohort Study. Finally we showed that, although the methylation of the two loci is not associated with longevity/mortality in the Leiden Longevity Study, ELOVL2 methylation is associated with cytomegalovirus status in nonagenarians, which could be informative of a higher number of replication events in a fraction of whole-blood cells. Collectively, these results indicate that ELOVL2 methylation is a marker of cell divisions occurring during human aging. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Low plasma selenium concentration is associated with elevated risk to neoplastic polyps of the colon

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clark, L.C.; Hixson, L.G.; Sampliner, R.E.

1991-03-11

A cross-sectional study was conducted to examine the relationship of selenium (Se) status and polyps incidence in a sequential series of 100 patients undergoing outpatient colonoscopies at the Tucson VA Hospital. Se was measured in plasma samples by electrothermal atomic absorption spectrophotometry with Zeeman background correction using a reduced palladium matrix modified. The activities of the Se-dependent enzyme glutathione peroxidase (SeGSHpx) were measured using H{sub 2}O{sub 2} as substrate in all plasma samples and in colonic mucosal biopsies obtained from some patients. The mean plasma Se concentration of patients without polyps was 134 ng/ml. Mean plasma Se levels of patientsmore » with only diminutive or large polyps were 127 ng/ml and 125 ng/ml; while patients with polyps of both sizes had a mean plasma Se level of 121 ng/ml. Patients with no reported history of cancer, neoplastic polyps or prior colonoscopy, showed an inverse association of plasma Se level and risk of benign colonic neoplasms. The age-adjusted odds ratio for neoplastic polyps was 3.8 for patients with plasma Se levels below vs. above the median value. This association was stronger for patients under 68 yrs of age than for older patients. Activities of SeGSHpx in plasma or colonic mucosa were not related to plasma Se level; however, smokers showed greater SeGSHpx activities than non-smokers. This study is the first to detect an association of Se status and risk to neoplastic polyps of the colon.« less

Function of plasma membrane microdomain-associated proteins during legume nodulation.

PubMed

Qiao, Zhenzhen; Libault, Marc

2017-10-03

Plasma membrane microdomains are plasma membrane sub-compartments enriched in sphingolipids and sterols, and composed by a specific set of proteins. They are involved in recognizing signal molecules, transducing these signals, and controlling endocytosis and exocytosis processes. In a recent study, applying biochemical and microscopic methods, we characterized the soybean GmFWL1 protein, a major regulator of soybean nodulation, as a new membrane microdomain-associated protein. Interestingly, upon rhizobia inoculation of the soybean root system, GmFWL1 and one of its interacting partners, GmFLOT2/4, both translocate to the root hair cell tip, the primary site of interaction and infection between soybean and Rhizobium. The role of GmFWL1 as a plasma membrane microdomain-associated protein is also supported by immunoprecipitation assays performed on soybean nodules, which revealed 178 GmFWL1 protein partners including a large number of microdomain-associated proteins such as GmFLOT2/4. In this addendum, we provide additional information about the identity of the soybean proteins repetitively identified as GmFWL1 protein partners. Their function is discussed especially in regard to plant-microbe interactions and microbial symbiosis. This addendum will provide new insights in the role of plasma membrane microdomains in regulating legume nodulation.

Plasma Cell Neoplasms (Including Multiple Myeloma)—Patient Version

Cancer.gov

Plasma cell neoplasms occur when abnormal plasma cells form cancerous tumors. When there is only one tumor, the disease is called a plasmacytoma. When there are multiple tumors, it is called multiple myeloma. Start here to find information on plasma cell neoplasms treatment, research, and statistics.

Alterations in plasma phosphorus, red cell 2,3-diphosphoglycerate and P50 following open heart surgery.

PubMed

Hasan, R A; Sarnaik, A P; Meert, K L; Dabbagh, S; Simpson, P; Makimi, M

1994-12-01

To evaluate changes in and the correlation between plasma phosphorus, red cell 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP), and P50 in children following heart surgery. Prospective, observational study with factorial design. A pediatric intensive care unit in a university hospital. Twenty children undergoing open heart surgery for congenital heart defects. None. Red cell 2,3-DPG and ATP, P50, plasma phosphorus, and arterial lactate were obtained before and at 1, 8, 16, 24, 48, and 72 hours after surgery. The amount of intravenous fluid and glucose administered, and age of blood utilized were documented. Variables were analyzed by repeated measure analysis of variance followed by paired t-tests. To investigate the relationship between variables at each time point, scatterplot matrices and correlation coefficients were obtained. There was a reduction in plasma phosphorus, red cell 2,3-DPG, and P50 and an increase in arterial lactate at 1, 8, 16, 24, 48, and 72 hours after surgery. Red cell 2,3-DPG correlated with P50 at 1, 8 and 16 hours. The decrease in the plasma phosphorus correlated with the amounts of intravenous fluid and glucose administered on the day of surgery and on the first and second postoperative days. The age of the blood utilized correlated with the decrease in red cell 2,3-DPG on the day of surgery. Reduction in red cell 2,3-DPG, P50, and plasma phosphorus occurs after open heart surgery in children. These changes can potentially contribute to impaired oxygen utilization in the postoperative period, when adequacy of tissue oxygenation is critical.

Treatment of prostate cancer cell lines and primary cells using low temperature plasma

NASA Astrophysics Data System (ADS)

O'Connell, Deborah; Hirst, Adam; Frame, Fiona F.; Maitland, Norman J.

2014-10-01

The mechanisms of cell death after plasma treatment of both benign and cancerous prostate epithelial cells are investigated. Prostate cancer tissue was obtained with patient consent from targeted needle core biopsies following radical prostatectomy. Primary cells were cultured from cancer tissue and plated onto a chamber slide at a density of 10,000 cells per well in 200 microliter of stem cell media (SCM). The treated sample was previously identified as Gleason grade 7 cancer through tissue histo-pathology. A dielectric barrier discharge (DBD) jet configuration, with helium as a carrier gas, and 0.3% O2 admixture was used for treating the cells. Reactive oxygen and nitrogen species (RONS) produced by the plasma are believed to be the main mediators of the plasma-cell interaction and response. We found the concentration of reactive oxygen species (ROS) induced inside the cells increased with plasma exposure. Exposure to the plasma for >3 minutes showed high levels of DNA damage compared to untreated and hydrogen peroxide controls. Cell viability and cellular recovery are also investigated and will be presented. All findings were common to both cell lines, suggesting the potential of LTP therapy for both benign and malignant disease.

Association of plasma selenium concentrations with total IGF-1 among older community-dwelling adults: the InCHIANTI study.

PubMed

Maggio, Marcello; Ceda, Gian Paolo; Lauretani, Fulvio; Bandinelli, Stefania; Dall'Aglio, Elisabetta; Guralnik, Jack M; Paolisso, Giuseppe; Semba, Richard D; Nouvenne, Antonio; Borghi, Loris; Ceresini, Graziano; Ablondi, Fabrizio; Benatti, Mario; Ferrucci, Luigi

2010-10-01

Insulin-like growth factor (IGF-1) stimulates cell proliferation and inhibits cell apoptosis. Recent studies underline its importance as anabolic hormone and nutritional marker in older individuals. IGF-1 synthesis and bioactivity are modulated by nutritional factors including selenium intake. However, whether circulating IGF-1 levels are positively influenced by plasma selenium, one of the most important human antioxidants, is still unknown. Selenium and total IGF-1 were measured in 951 men and women ≥ 65 years from the InCHIANTI study, Tuscany, Italy. Means (SD) of plasma selenium and total IGF-1 were 0.95 (0.15) μmol/L and 113.4 (31.2)ng/mL, respectively. After adjustment for age and sex, selenium levels were positively associated with total IGF-1 (β±SE: 43.76±11.2, p=0.0001). After further adjustment for total energy and alcohol intake, serum alanine aminotransferase (ALT), congestive heart failure, selenium remained significantly associated with IGF-1 (β±SE: 36.7±12.2, p=0.003). The association was still significant when IL-6 was introduced in the model (β±SE: 40.1±12.0, p=0.0008). We found an independent, positive and significant association between selenium and IGF-1 serum levels in community dwelling older adults. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Association of Plasma Selenium Concentrations with Total IGF-1 Among Older Community-Dwelling Adults: the InCHIANTI Study

PubMed Central

Maggio, Marcello; Ceda, Gian Paolo; Lauretani, Fulvio; Bandinelli, Stefania; Dall'Aglio, Elisabetta; Guralnik, Jack M.; Paolisso, Giuseppe; Semba, Richard D.; Nouvenne, Antonio; Borghi, Loris; Ceresini, Graziano; Ablondi, Fabrizio; Benatti, Mario; Ferrucci, Luigi

2011-01-01

Background and Aims Insulin-like growth factor (IGF-1) stimulates cell proliferation and inhibits cell apoptosis. Recent studies underline its importance as anabolic hormone and nutritional marker in older individuals. IGF-1 synthesis and bioactivity are modulated by nutritional factors including selenium intake. However, whether circulating IGF-1 levels are positively influenced by plasma selenium, one of the most important human antioxidants, is still unknown. Methods Selenium and total IGF-1 were measured in 951 men and women ≥65 years from the InCHIANTI study, Tuscany, Italy. Results Means (SD) of plasma selenium and total IGF-1 were 0.95 (0.15) µmol/L and 113.4 (31.2) ng/mL, respectively. After adjustment for age and sex, selenium levels were positively associated with total IGF-1 (ß ± SE: 43.76±11.2, p=0.0001).After further adjustment for total energy and alcohol intake, serum alanine amino transferase (ALT), congestive heart failure, selenium remained significantly associated with IGF-1 (β ± SE: 36.7 ± 12.2, p=0.003). The association was still significant when IL-6 was introduced in the model (β ± SE: 40.1 ± 12.0, p=0.0008). Conclusions We found an independent, positive and significant association between selenium and IGF-1 serum levels in community dwelling older adults. PMID:20416996

Epigenetic regulation of hematopoietic stem cell aging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116

2014-12-10

Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and playmore » a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.« less

Lymphatic Muscle Cells in Rat Mesenteric Lymphatic Vessels of Various Ages

PubMed Central

Bridenbaugh, Eric A.; Nizamutdinova, Irina Tsoy; Jupiter, Daniel; Nagai, Takashi; Thangaswamy, Sangeetha; Chatterjee, Victor

2013-01-01

Abstract Background Recent studies on aging-associated changes in mesenteric lymph flow in situ demonstrated predominance of the severe negative chronotropic effect of aging on the contractility of aged mesenteric lymphatic vessels (MLV). At the same time, contraction amplitude of the aged vessels was only slightly diminished by aging and can be rapidly stimulated within 5–15 minutes. However, the detailed quantitative evaluation of potential aging-associated changes in muscle cells investiture in MLV has never been performed. Methods and Results In this study we, for the first time, performed detailed evaluation of muscle cells investiture in MLV in reference to the position of lymphatic valve in different zones of lymphangion within various age groups (3-mo, 9-mo and 24-mo Fischer-344 rats). Using visual and quantitative analyses of the images of MLV immunohistochemically labeled for actin, we confirmed that the zones located close upstream (pre-valve zones) and above lymphatic valves (valve zones) possess the lowest investiture of lymphatic muscle cells. Most of the high muscle cells investiture zones exist downstream to the lymphatic valve (post-valve zones). The muscle cells investiture of these zones is not affected by aging, while pre-valve and valve zones demonstrate significant aging-associated decrease in muscle cells investiture. Conclusions The low muscle cells investiture zones in lymphatic vessels consist of predominantly longitudinally oriented muscle cells which are positioned in pre-valve and valve zones and connect adjacent lymphangions. These cells may provide important functional impact on the biomechanics of the lymphatic valve gating and electrical coupling between lymphangions, while their aging-associated changes may delimit adaptive reserves of aged lymphatic vessels. PMID:23531183

Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes.

PubMed

Liang, Xiaozhen; Collins, Christopher M; Mendel, Justin B; Iwakoshi, Neal N; Speck, Samuel H

2009-11-01

Gammaherpesviruses chronically infect their host and are tightly associated with the development of lymphoproliferative diseases and lymphomas, as well as several other types of cancer. Mechanisms involved in maintaining chronic gammaherpesvirus infections are poorly understood and, in particular, little is known about the mechanisms involved in controlling gammaherpesvirus reactivation from latently infected B cells in vivo. Recent evidence has linked plasma cell differentiation with reactivation of the human gammaherpesviruses EBV and KSHV through induction of the immediate-early viral transcriptional activators by the plasma cell-specific transcription factor XBP-1s. We now extend those findings to document a role for a gammaherpesvirus gene product in regulating plasma cell differentiation and thus virus reactivation. We have previously shown that the murine gammaherpesvirus 68 (MHV68) gene product M2 is dispensable for virus replication in permissive cells, but plays a critical role in virus reactivation from latently infected B cells. Here we show that in mice infected with wild type MHV68, virus infected plasma cells (ca. 8% of virus infected splenocytes at the peak of viral latency) account for the majority of reactivation observed upon explant of splenocytes. In contrast, there is an absence of virus infected plasma cells at the peak of latency in mice infected with a M2 null MHV68. Furthermore, we show that the M2 protein can drive plasma cell differentiation in a B lymphoma cell line in the absence of any other MHV68 gene products. Thus, the role of M2 in MHV68 reactivation can be attributed to its ability to manipulate plasma cell differentiation, providing a novel viral strategy to regulate gammaherpesvirus reactivation from latently infected B cells. We postulate that M2 represents a new class of herpesvirus gene products (reactivation conditioners) that do not directly participate in virus replication, but rather facilitate virus reactivation by

Increased plasma proline concentrations are associated with sarcopenia in the elderly

PubMed Central

Adachi, Yusuke; Imaizumi, Akira; Hakamada, Tomomi; Abe, Yasuko; Kaneko, Eiji; Takahashi, Soiciro; Shimokado, Kentaro

2017-01-01

Background and purpose Metabolome analyses have shown that plasma amino acid profiles reflect various pathological conditions, such as cancer and diabetes mellitus. It remains unclear, however, whether plasma amino acid profiles change in patients with sarcopenia. This study therefore aimed to investigate whether sarcopenia-specific changes occur in plasma amino acid profiles. Methods A total of 153 community-dwelling and seven institutionalized elderly individuals (56 men, 104 women; mean age, 77.7±7.0 years) were recruited for this cross-sectional analysis. We performed a comprehensive geriatric assessment, which included an evaluation of hand grip strength, gait speed, muscle mass and blood chemistry, including the concentration of 18 amino acids. Results Twenty-eight of the 160 participants met the criteria for sarcopenia established by the Asian Working Group on Sarcopenia in Older People. Univariate analysis revealed associations between the presence of sarcopenia and a higher plasma concentration of proline and glutamine, lower concentrations of histidine and tryptophan. Multivariable analysis revealed that a higher concentration of proline was the only variable independently associated with sarcopenia. Conclusions The plasma concentration of proline may be useful for understanding the underlying pathophysiology of sarcopenia. PMID:28934309

Increased plasma proline concentrations are associated with sarcopenia in the elderly.

PubMed

Toyoshima, Kenji; Nakamura, Marie; Adachi, Yusuke; Imaizumi, Akira; Hakamada, Tomomi; Abe, Yasuko; Kaneko, Eiji; Takahashi, Soiciro; Shimokado, Kentaro

2017-01-01

Metabolome analyses have shown that plasma amino acid profiles reflect various pathological conditions, such as cancer and diabetes mellitus. It remains unclear, however, whether plasma amino acid profiles change in patients with sarcopenia. This study therefore aimed to investigate whether sarcopenia-specific changes occur in plasma amino acid profiles. A total of 153 community-dwelling and seven institutionalized elderly individuals (56 men, 104 women; mean age, 77.7±7.0 years) were recruited for this cross-sectional analysis. We performed a comprehensive geriatric assessment, which included an evaluation of hand grip strength, gait speed, muscle mass and blood chemistry, including the concentration of 18 amino acids. Twenty-eight of the 160 participants met the criteria for sarcopenia established by the Asian Working Group on Sarcopenia in Older People. Univariate analysis revealed associations between the presence of sarcopenia and a higher plasma concentration of proline and glutamine, lower concentrations of histidine and tryptophan. Multivariable analysis revealed that a higher concentration of proline was the only variable independently associated with sarcopenia. The plasma concentration of proline may be useful for understanding the underlying pathophysiology of sarcopenia.

Exosomes Secreted by HeLa Cells Shuttle on Their Surface the Plasma Membrane-Associated Sialidase NEU3.

PubMed

Paolini, Lucia; Orizio, Flavia; Busatto, Sara; Radeghieri, Annalisa; Bresciani, Roberto; Bergese, Paolo; Monti, Eugenio

2017-12-05

Sialidases are glycohydrolases that remove terminal sialic acid residues from oligosaccharides, glycolipids, and glycoproteins. The plasma membrane-associated sialidase NEU3 is involved in the fine-tuning of sialic acid-containing glycans directly on the cell surface and plays relevant roles in important biological phenomena such as cell differentiation, molecular recognition, and cancer transformation. Extracellular vesicles are membranous structures with a diameter of 0.03-1 μm released by cells and can be detected in blood, urine, and culture media. Among extracellular vesicles, exosomes play roles in intercellular communication and maintenance of several physiological and pathological conditions, including cancer, and could represent a useful diagnostic tool for personalized nanomedicine approaches. Using inducible expression of the murine form of NEU3 in HeLa cells, a study of the association of the enzyme with exosomes released in the culture media has been performed. Briefly, NEU3 is associated with highly purified exosomes and localizes on the external leaflet of these nanovesicles, as demonstrated by enzyme activity measurements, Western blot analysis, and dot blot analysis using specific protein markers. On the basis of these results, it is plausible that NEU3 activity on exosome glycans enhances the dynamic biological behavior of these small extracellular vesicles by modifying the negative charge and steric hindrance of their glycocalyx. The presence of NEU3 on the exosomal surface could represent a useful marker for the detection of these nanovesicles and a tool for improving our understanding of the biology of these important extracellular carriers in physiological and pathological conditions.

Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4

PubMed Central

Ochiai, Kyoko; Maienschein-Cline, Mark; Simonetti, Giorgia; Chen, Jianjun; Rosenthal, Rebecca; Brink, Robert; Chong, Anita S.; Klein, Ulf; Dinner, Aaron R.; Singh, Harinder; Sciammas, Roger

2013-01-01

Summary The transcription factor IRF4 regulates immunoglobulin class switch recombination and plasma cell differentiation. Its differing concentrations appear to regulate mutually antagonistic programs of B and plasma cell gene expression. We show IRF4 to be also required for generation of germinal center (GC) B cells. Its transient expression in vivo induced the expression of key GC genes including Bcl6 and Aicda. In contrast, sustained and higher concentrations of IRF4 promoted the generation of plasma cells while antagonizing the GC fate. IRF4 co-bound with the transcription factors PU.1 or BATF to Ets or AP-1 composite motifs, associated with genes involved in B cell activation and the GC response. At higher concentrations IRF4 binding shifted to interferon sequence response motifs; these enriched for genes involved in plasma cell differentiation. Our results support a model of “kinetic control” in which signaling induced dynamics of IRF4 in activated B cells control their cell fate outcomes. PMID:23684984

Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood.

PubMed

Ebner, Natalie C; Lin, Tian; Muradoglu, Melis; Weir, Devon H; Plasencia, Gabriela M; Lillard, Travis S; Pournajafi-Nazarloo, Hossein; Cohen, Ronald A; Sue Carter, C; Connelly, Jessica J

2018-02-02

The neuropeptide oxytocin (OT) has been implicated in a wide range of affiliative processes. OT exerts its functions via OT receptors, which are encoded by the oxytocin receptor gene (OXTR). Epigenetic modification of OXTR through the process of DNA methylation has been associated with individual differences in behavioral phenotypes. Specifically, lower levels of OXTR methylation have been linked to better social and affective functioning. However, research on epigenetic mechanisms of OXTR is scarce in non-clinical populations, and even less is known about epigenetic variability across adulthood. The present study assessed methylation levels at OXTR CpG site -934 and plasma OT levels in 22 young (20-31 years, M = 23.6) and 34 older (63-80 years, M = 71.4) participants. Lower levels of OXTR methylation and higher plasma OT levels were associated with less self-reported attachment anxiety in young but not older participants, with largely independent contributions of OXTR methylation and plasma OT levels. In contrast, in the overall sample, lower levels of OXTR methylation were associated with higher self-reported attachment avoidance. Age analysis suggested that these results were largely driven by young adults. Plasma OT levels were unrelated to attachment avoidance. Taken together, these findings support the emerging notion in the literature that epigenetic properties of OXTR, in addition to endogenous OT levels, are related to adult attachment. Further, the age effects observed in the associations between OXTR methylation, plasma OT, and adult attachment emphasize the importance of adopting a developmental perspective when studying properties of the OT system and their relation to affiliative processes. Findings contribute to growing evidence suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships. Copyright © 2018 Elsevier B

Proteomic profiling of human plasma exosomes identifies PPAR{gamma} as an exosome-associated protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Looze, Christopher; Yui, David; Leung, Lester

Exosomes are nanovesicles that are released from cells as a mechanism of cell-free intercellular communication. Only a limited number of proteins have been identified from the plasma exosome proteome. Here, we developed a multi-step fractionation scheme incorporating gel exclusion chromatography, rate zonal centrifugation through continuous sucrose gradients, and high-speed centrifugation to purify exosomes from human plasma. Exosome-associated proteins were separated by SDS-PAGE and 66 proteins were identified by LC-MS/MS, which included both cellular and extracellular proteins. Furthermore, we identified and characterized peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), a nuclear receptor that regulates adipocyte differentiation and proliferation, as well as immune and inflammatorymore » cell functions, as a novel component of plasma-derived exosomes. Given the important role of exosomes as intercellular messengers, the discovery of PPAR{gamma} as a component of human plasma exosomes identifies a potential new pathway for the paracrine transfer of nuclear receptors.« less

The slippery slope of hematopoietic stem cell aging.

PubMed

Wahlestedt, Martin; Bryder, David

2017-12-01

The late stages of life, in most species including humans, are associated with a decline in the overall maintenance and health of the organism. This applies also to the hematopoietic system, where aging is not only associated with an increased predisposition for hematological malignancies, but also identified as a strong comorbidity factor for other diseases. Research during the last two decades has proposed that alterations at the level of hematopoietic stem cells (HSCs) might be a root cause for the hematological changes observed with age. However, the recent realization that not all HSCs are alike with regard to fundamental stem cell properties such as self-renewal and lineage potential has several implications for HSC aging, including the synchrony and the stability of the aging HSC state. To approach HSC aging from a clonal perspective, we recently took advantage of technical developments in cellular barcoding and combined this with the derivation of induced pluripotent stem cells (iPSCs). This allowed us to selectively approach HSCs functionally affected by age. The finding that such iPSCs were capable of fully regenerating multilineage hematopoiesis upon morula/blastocyst complementation provides compelling evidence that many aspects of HSC aging can be reversed, which indicates that a central mechanism underlying HSC aging is a failure to uphold the epigenomes associated with younger age. Here we discuss these findings in the context of the underlying causes that might influence HSC aging and the requirements and prospects for restoration of the aging HSC epigenome. Copyright © 2017 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Seminal plasma induces global transcriptomic changes associated with cell migration, proliferation and viability in endometrial epithelial cells and stromal fibroblasts.

PubMed

Chen, Joseph C; Johnson, Brittni A; Erikson, David W; Piltonen, Terhi T; Barragan, Fatima; Chu, Simon; Kohgadai, Nargis; Irwin, Juan C; Greene, Warner C; Giudice, Linda C; Roan, Nadia R

2014-06-01

How does seminal plasma (SP) affect the transcriptome of human primary endometrial epithelial cells (eEC) and stromal fibroblasts (eSF)? Exposure of eEC and eSF to SP in vitro increases expression of genes and secreted proteins associated with cellular migration, proliferation, viability and inhibition of cell death. Studies in both humans and animals suggest that SP can access and induce physiological changes in the upper female reproductive tract (FRT), which may participate in promoting reproductive success. This is a cross sectional study involving control samples versus treatment. SP (pooled from twenty donors) was first tested for dose- and time-dependent cytotoxic effects on eEC and eSF (n = 4). As exposure of eEC or eSF to 1% SP for 6 h proved to be non-toxic, a second set of eEC/eSF samples (n = 4) was treated under these conditions for transcriptome, protein and functional analysis. With a third set of samples (n = 3), we further compared the transcriptional response of the cells to SP versus fresh semen. eEC and eSF were isolated from endometrial biopsies from women of reproductive age undergoing benign gynecologic procedures and maintained in vitro. RNA was isolated and processed for microarray studies to analyze global transcriptomic changes. Secreted factors in conditioned media from SP-treated cells were analyzed by Luminex and for the ability to stimulate migration of CD14+ monocytes and CD4+ T cells. Pathway identifications were determined using the Z-scoring system in Ingenuity Pathways Analysis (Z scores ≥|1.5|). SP induced transcriptomic changes (P < 0.05) associated with promoting leukocyte and endothelial cell recruitment, and proliferation of eEC and eSF. Cell viability pathways were induced, while those associated with cell death were suppressed (P < 0.05). SP and fresh semen induced similar sets of pathways, suggesting that SP can model the signaling effects of semen in the endometrium. SP also induced secretion of pro-inflammatory and

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases

PubMed Central

Davalli, Pierpaola; Mitic, Tijana; Caporali, Andrea; Lauriola, Angela; D'Arca, Domenico

2016-01-01

The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS) and/or Reactive Nitrosative Species (RNS). Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging. PMID:27247702

At the border: the plasma membrane-cell wall continuum.

PubMed

Liu, Zengyu; Persson, Staffan; Sánchez-Rodríguez, Clara

2015-03-01

Plant cells rely on their cell walls for directed growth and environmental adaptation. Synthesis and remodelling of the cell walls are membrane-related processes. During cell growth and exposure to external stimuli, there is a constant exchange of lipids, proteins, and other cell wall components between the cytosol and the plasma membrane/apoplast. This exchange of material and the localization of cell wall proteins at certain spots in the plasma membrane seem to rely on a particular membrane composition. In addition, sensors at the plasma membrane detect changes in the cell wall architecture, and activate cytoplasmic signalling schemes and ultimately cell wall remodelling. The apoplastic polysaccharide matrix is, on the other hand, crucial for preventing proteins diffusing uncontrollably in the membrane. Therefore, the cell wall-plasma membrane link is essential for plant development and responses to external stimuli. This review focuses on the relationship between the cell wall and plasma membrane, and its importance for plant tissue organization. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Effects of intra-articular injection of mesenchymal stem cells associated with platelet-rich plasma in a rabbit model of osteoarthritis.

PubMed

Hermeto, L C; DeRossi, R; Oliveira, R J; Pesarini, J R; Antoniolli-Silva, A C M B; Jardim, P H A; Santana, A E; Deffune, E; Rinaldi, J C; Justulin, L A

2016-09-02

The current study aims to evaluate the macroscopic and histological effects of autologous mesenchymal stem cells (MSC) and platelet-rich plasma on knee articular cartilage regeneration in an experimental model of osteoarthritis. Twenty-four rabbits were randomly divided into four groups: control group, platelet-rich plasma group, autologous MSC undifferentiated group, and autologous MSC differentiated into chondrocyte group. Collagenase solution was used to induce osteoarthritis, and treatments were applied to each group at 6 weeks following osteoarthritis induction. After 60 days of therapy, the animals were euthanized and the articular surfaces were subjected to macroscopic and histological evaluations. The adipogenic, chondrogenic, and osteogenic differentiation potentials of MSCs were evaluated. Macroscopic and histological examinations revealed improved tissue repair in the MSC-treated groups. However, no difference was found between MSC-differentiated and undifferentiated chondrocytes. We found that MSCs derived from adipose tissue and platelet-rich plasma were associated with beneficial effects in articular cartilage regeneration during experimental osteoarthritis.

NF-κB activation impairs somatic cell reprogramming in ageing.

PubMed

Soria-Valles, Clara; Osorio, Fernando G; Gutiérrez-Fernández, Ana; De Los Angeles, Alejandro; Bueno, Clara; Menéndez, Pablo; Martín-Subero, José I; Daley, George Q; Freije, José M P; López-Otín, Carlos

2015-08-01

Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

Proximity to a Major Road and Plasma Cytokines in School-Aged Children

PubMed Central

Rosser, Franziska; Forno, Erick; Brehm, John; Han, Yueh-Ying; Boutaoui, Nadia; Colón-Semidey, Angel; Alvarez, María; Acosta-Pérez, Edna; Kurland, Kristen S.; Alcorn, John F.; Canino, Glorisa

2016-01-01

Traffic-related air pollution (TRAP) may affect immune responses, including those in the TH2 and TH17 pathways. To examine whether TRAP is associated with plasma level of TH17-, TH1-, and TH2-related cytokines in children with and without asthma, a cross-sectional study of 577 children (ages 6–14 years) with (n = 294) and without (n = 283) asthma in San Juan (Puerto Rico) was performed. Residential distance to a major road was estimated using geocoded home addresses for study participants. A panel of 14 cytokines, enriched for the TH17 pathway, was measured in plasma. Asthma was defined as physician-diagnosed asthma and current wheeze. Multivariable linear regression was used to examine the association of residential distance to a major road (a marker of TRAP), asthma, and cytokine levels. Among all participating children, residential proximity to a major road was significantly associated with increased plasma level of IL-31, even after adjustment for relevant covariates and correction for multiple testing. The presence of asthma modified the estimated effect of the residential distance to a major road on plasma TNF-α (P for interaction = 0.00047). Although living farther from a major road was significantly associated with lower TNF-α level in control subjects, no such decrease was seen in children with asthma. In a direct comparison of cases and control subjects, children with asthma had significantly higher levels of IL-1β, IL-22, and IL-33 than control subjects. TRAP is associated with increased levels of proinflammatory cytokines among Puerto Rican children, who belong to an ethnic group with high risk for asthma. PMID:28265480

Low Temperature Plasma Kills SCaBER Cancer Cells

NASA Astrophysics Data System (ADS)

Barekzi, Nazir; van Way, Lucas; Laroussi, Mounir

2013-09-01

Squamous cell carcinoma of the bladder is a rare type of bladder cancer that forms as a result of chronic irritation of the epithelial lining of the bladder. The cell line used in this study is SCaBER (ATCC® HTB-3™) derived from squamous cell carcinoma of the human urinary bladder. Current treatments of bladder cancer include surgery, radiation and chemotherapy. However, the cost of these treatments, the potential toxicity of the chemotherapeutic agents and the systemic side-effects warrant an alternative to current cancer treatment. This paper represents preliminary studies to determine the effects of biologically tolerant plasma (BTP) on a cell line of human bladder cancer cells. Previous work by our group using the plasma pencil revealed the efficacy of BTP on leukemia cells suspended in solution. Based on these earlier findings we hypothesized that the plasma exposure would elicit a similar programmed cell death in the SCaBER cells. Trypan blue exclusion and MTT assays revealed the cell killing after exposure to BTP. Our study indicates that low temperature plasma generated by ionizing helium gas and the reactive species may be a suitable and safe alternative for cancer therapy.

γ/δ T cell subsets in human aging using the classical α/β T cell model.

PubMed

Vasudev, Anusha; Ying, Crystal Tan Tze; Ayyadhury, Shamini; Puan, Kia Joo; Andiappan, Anand Kumar; Nyunt, Ma Shwe Zin; Shadan, Nurhidaya Binte; Mustafa, Seri; Low, Ivy; Rotzschke, Olaf; Fulop, Tamas; Ng, Tze Pin; Larbi, Anis

2014-10-01

Aging is associated with an increased susceptibility to infections and diseases. It has also been associated with reduced functionality and altered distribution of immune cells, especially T cells. Whereas classical α/β T cells, especially CD8(+) T cells, were shown to be highly susceptible to aging, the effects of viral persistent stimulations on the fate of γ/δ T cells are much less documented. Healthy, elderly individuals of Chinese ethnical background were recruited under the aegis of SLAS-II. In this observational study, γ/δ T cell populations were characterized by flow cytometry and compared with the α/β CD4(+) and CD8(+) T cells in elderly and young controls. In our study, we identified a reduced frequency of γ/δ T cells but not α/β T cells with aging. The classical markers of α/β T cell aging, including CD28, CD27, and CD57, did not prove significant for γ/δ T cells. The extreme range of expression of these markers in γ/δ T cells was responsible for the lack of relationship between γ/δ T cell subsets, CD4/CD8 ratio, and anti-CMV titers that was significant for α/β T cells and, especially, CD8(+) T cells. Although markers of aging for γ/δ T cells are not clearly identified, our data collectively suggest that the presence of CD27 γ/δ T cells is associated with markers of α/β T cell aging. © 2014 Society for Leukocyte Biology.

Clinical and Prognostic Effect of Plasma Fibrinogen in Renal Cell Carcinoma: A Meta-Analysis.

PubMed

Tian, Yuejun; Hong, Mei; Jing, Suoshi; Liu, Xingchen; Wang, Hanzhang; Wang, Xinping; Kaushik, Dharam; Rodriguez, Ronald; Wang, Zhiping

2017-01-01

Background . Although numerous studies have shown that plasma fibrinogen is linked to renal cell carcinoma (RCC) risk, the consistency and magnitude of the effect of plasma fibrinogen are unclear. The aim of the study was to explore the association between plasma fibrinogen and RCC prognosis. Methods . An electronic search of Embase, PubMed/MEDLINE, and the Cochrane databases was performed to identify relevant studies published prior to June 1, 2016. Results . A total of 3744 patients with RCC from 7 published studies were included in the meta-analysis. The prognostic and clinical relevance of plasma fibrinogen are evaluated in RCC patients. Statistical significance of the combined hazard ratio (HR) was detected for overall survival, cancer-specific survival, and disease-free survival. Our pooled results showed that elevated plasma fibrinogen was significantly associated with clinical stage and Fuhrman grading. The level of plasma fibrinogen was not found to be associated with tumor type and gender. Conclusions . Elevated plasma fibrinogen is a strong indicator of poorer prognosis of patients with RCC, whereas the plasma fibrinogen is not significantly associated with tumor type. Therefore, plasma fibrinogen could be used in patients with RCC for risk stratification and decision providing a proper therapeutic strategy.

Unmethylated-maspin DNA in maternal plasma is associated with severe preeclampsia.

PubMed

Qi, Yan-Hua; Teng, Fei; Zhou, Qi; Liu, Yu-Xin; Wu, Jin-Fang; Yu, Shan-Shan; Zhang, Xin; Ma, Miao-Yan; Zhou, Ni; Chen, Li-Juan

2015-09-01

Cell-free fetal DNA in maternal plasma is associated with complications of pregnancy, including preeclampsia. Determination of levels is affected by fetal gender and genetic polymorphisms. Unmethylated maspin (u-maspin) is present in the placenta, and is placental-specific. The purpose of this study was to determine whether u-maspin DNA in maternal blood could serve as a marker of preeclampsia by measuring levels in different trimesters of normal pregnancies and in those complicated by preeclampsia. This case-control study was set in a tertiary care hospital. The population consisted of 45 women with normal pregnancies (15 in the 1st trimester, 15 in the 2nd trimester, 15 in the 3rd trimester), 20 women with mild preeclampsia, 25 women with severe preeclampsia, and six women with gestational trophoblastic disease. Peripheral blood was collected and methylation-specific PCR and fluorescence quantitative PCR were performed to measure the content of u-maspin DNA in maternal blood. U-maspin DNA was 5.5-fold higher in women with severe preeclampsia than in those with a normal 3rd trimester pregnancy (p < 0.05). During normal pregnancy, u-maspin DNA in maternal plasma tended to increase with advancing gestational age (p = 0.06). U-maspin DNA was not detected in healthy non-pregnant women or those with gestational trophoblastic disease. U-maspin DNA in maternal blood is associated with severe preeclampsia. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance.

PubMed

Guia, Sophie; Jaeger, Baptiste N; Piatek, Stefan; Mailfert, Sébastien; Trombik, Tomasz; Fenis, Aurore; Chevrier, Nicolas; Walzer, Thierry; Kerdiles, Yann M; Marguet, Didier; Vivier, Eric; Ugolini, Sophie

2011-04-05

Natural killer (NK) cell tolerance to self is partly ensured by major histocompatibility complex (MHC) class I-specific inhibitory receptors on NK cells, which dampen their reactivity when engaged. However, NK cells that do not detect self MHC class I are not autoreactive. We used dynamic fluorescence correlation spectroscopy to show that MHC class I-independent NK cell tolerance in mice was associated with the presence of hyporesponsive NK cells in which both activating and inhibitory receptors were confined in an actin meshwork at the plasma membrane. In contrast, the recognition of self MHC class I by inhibitory receptors "educated" NK cells to become fully reactive, and activating NK cell receptors became dynamically compartmentalized in membrane nanodomains. We propose that the confinement of activating receptors at the plasma membrane is pivotal to ensuring the self-tolerance of NK cells.

Mitochondrial and Plasma Membrane Pools of Stomatin-Like Protein 2 Coalesce at the Immunological Synapse during T Cell Activation

PubMed Central

Christie, Darah A.; Kirchhof, Mark G.; Vardhana, Santosh; Dustin, Michael L.; Madrenas, Joaquín

2012-01-01

Stomatin-like protein 2 (SLP-2) is a member of the stomatin – prohibitin – flotillin – HflC/K (SPFH) superfamily. Recent evidence indicates that SLP-2 is involved in the organization of cardiolipin-enriched microdomains in mitochondrial membranes and the regulation of mitochondrial biogenesis and function. In T cells, this role translates into enhanced T cell activation. Although the major pool of SLP-2 is associated with mitochondria, we show here that there is an additional pool of SLP-2 associated with the plasma membrane of T cells. Both plasma membrane-associated and mitochondria-associated pools of SLP-2 coalesce at the immunological synapse (IS) upon T cell activation. SLP-2 is not required for formation of IS nor for the re-localization of mitochondria to the IS because SLP-2-deficient T cells showed normal re-localization of these organelles in response to T cell activation. Interestingly, upon T cell activation, we found the surface pool of SLP-2 mostly excluded from the central supramolecular activation complex, and enriched in the peripheral area of the IS where signalling TCR microclusters are located. Based on these results, we propose that SLP-2 facilitates the compartmentalization not only of mitochondrial membranes but also of the plasma membrane into functional microdomains. In this latter location, SLP-2 may facilitate the optimal assembly of TCR signalosome components. Our data also suggest that there may be a net exchange of membrane material between mitochondria and plasma membrane, explaining the presence of some mitochondrial proteins in the plasma membrane. PMID:22623988

High levels of circulating triiodothyronine induce plasma cell differentiation.

PubMed

Bloise, Flavia Fonseca; Oliveira, Felipe Leite de; Nobrega, Alberto Félix; Vasconcellos, Rita; Cordeiro, Aline; Paiva, Luciana Souza de; Taub, Dennis D; Borojevic, Radovan; Pazos-Moura, Carmen Cabanelas; Mello-Coelho, Valéria de

2014-03-01

The effects of hyperthyroidism on B-cell physiology are still poorly known. In this study, we evaluated the influence of high-circulating levels of 3,5,3'-triiodothyronine (T3) on bone marrow, blood, and spleen B-cell subsets, more specifically on B-cell differentiation into plasma cells, in C57BL/6 mice receiving daily injections of T3 for 14 days. As analyzed by flow cytometry, T3-treated mice exhibited increased frequencies of pre-B and immature B-cells and decreased percentages of mature B-cells in the bone marrow, accompanied by an increased frequency of blood B-cells, splenic newly formed B-cells, and total CD19(+)B-cells. T3 administration also promoted an increase in the size and cellularity of the spleen as well as in the white pulp areas of the organ, as evidenced by histological analyses. In addition, a decreased frequency of splenic B220(+) cells correlating with an increased percentage of CD138(+) plasma cells was observed in the spleen and bone marrow of T3-treated mice. Using enzyme-linked immunospot assay, an increased number of splenic immunoglobulin-secreting B-cells from T3-treated mice was detected ex vivo. Similar results were observed in mice immunized with hen egg lysozyme and aluminum adjuvant alone or together with treatment with T3. In conclusion, we provide evidence that high-circulating levels of T3 stimulate plasma cytogenesis favoring an increase in plasma cells in the bone marrow, a long-lived plasma cell survival niche. These findings indicate that a stimulatory effect on plasma cell differentiation could occur in untreated patients with Graves' disease.

Paraneoplastic scleroderma-like tissue reactions in the setting of an underlying plasma cell dyscrasia: a report of 10 cases.

PubMed

Magro, Cynthia M; Iwenofu, Hans; Nuovo, Gerard J

2013-07-01

Systemic plasma cell dyscrasias have diverse manifestations in the skin and include an inflammatory paraneoplastic process. We encountered cases of scleroderma and eosinophilic fasciitis in the setting of an underlying plasma cell dyscrasia. Ten cases of scleroderma-like tissue reactions in the setting of an underlying plasma cell dyscrasia were encountered. The biopsies were stained for Transforming growth factor (Transforming growth factor) beta, IgG4, kappa, and lambda. Patients presented with a sclerodermoid reaction represented by eosinophilic fasciitis (5 cases), morphea (3 cases), and systemic scleroderma (2 cases). The mean age of presentation was 70 years with a striking female predominance (4:1). Acral accentuation was noted in 8 cases. In 6 of the cases, the cutaneous sclerosis antedated (4 cases) by weeks to 2 years or occurred concurrently (2 cases) with the initial diagnosis of the plasma cell. The biopsies showed changes typical of eosinophilic fasciitis and/or scleroderma. In 5 cases, light chain-restricted plasma cells were present on the biopsy. There was staining of the plasma cells for Transforming growth factor beta in 3 out of 5 cases tested. In any older patient presenting with a sudden onset of eosinophilic fasciitis or scleroderma especially with acral accentuation, investigations should be conducted in regards to an underlying plasma cell dyscrasia.

Predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men.

PubMed

Wang, Yi-Xin; Liu, Chong; Chen, Ying-Jun; Chen, Heng-Gui; Yang, Pan; Wang, Peng; Huang, Li-Li; Ai, Song-Hua; Duan, Peng; Pan, An; Zeng, Qiang; Lu, Wen-Qing

2018-02-01

Certain phthalates are suspected to be endocrine disruptors that are adversely associated with male reproductive health. However, the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men have not been thoroughly studied. To investigate the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among adult Chinese males. We measured mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-octyl phthalate (MOP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations in seminal plasma and repeated spot-urine samples from 687 men who visited a reproductive center. Mixed-effect models were used to examine the associations of sociodemographic, lifestyle and medical factors with urinary metabolite concentrations. Linear regression models were used to identify predictors of metabolite concentrations in seminal plasma and correlations between metabolite concentrations in spot urine samples and seminal plasma. Measurements taken from spot urine samples poorly predicted same-day seminal plasma concentrations (all R 2 <0.10). Inverse associations were observed between education level and urinary MBP and MEOHP and between household income and urinary MMP; receiving intravenous infusion therapy was associated with increased urinary MBP, MEHHP and MEOHP, use of facial cleanser/cream was associated with increased MEP, and smoking was associated with increased MEHP. The predictors of metabolite concentrations in seminal plasma differed from those in urine, except for the association of intravenous infusion therapy with MBP. BMI was associated with increased seminal plasma MBP, MEHP and MEOHP, smoking was associated with increased MEP, and contact with plastics was associated with increased MEOHP. Phthalate metabolite

Miniature Dielectric Barrier Discharge Nonthermal Plasma Induces Apoptosis in Lung Cancer Cells and Inhibits Cell Migration.

PubMed

Karki, Surya B; Yildirim-Ayan, Eda; Eisenmann, Kathryn M; Ayan, Halim

2017-01-01

Traditional cancer treatments like radiotherapy and chemotherapy have drawbacks and are not selective for killing only cancer cells. Nonthermal atmospheric pressure plasmas with dielectric barrier discharge (DBD) can be applied to living cells and tissues and have emerged as novel tools for localized cancer therapy. The purpose of this study was to investigate the different effects caused by miniature DBD (mDBD) plasma to A549 lung cancer cells. In this study, A549 lung cancer cells cultured in 12 well plates were treated with mDBD plasma for specified treatment times to assess the changes in the size of the area of cell detachment, the viability of attached or detached cells, and cell migration. Furthermore, we investigated an innovative mDBD plasma-based therapy for localized treatment of lung cancer cells through apoptotic induction. Our results indicate that plasma treatment for 120 sec causes apoptotic cell death in 35.8% of cells, while mDBD plasma treatment for 60 sec, 30 sec, or 15 sec causes apoptotic cell death in 20.5%, 14.1%, and 6.3% of the cell population, respectively. Additionally, we observed reduced A549 cell migration in response to mDBD plasma treatment. Thus, mDBD plasma system can be a viable platform for localized lung cancer therapy.

Plasma Protein Oxidation and Its Correlation with Antioxidant Potential During Human Aging

PubMed Central

Pandey, Kanti Bhooshan; Mehdi, Mohd Murtaza; Maurya, Pawan Kumar; Rizvi, Syed Ibrahim

2010-01-01

Previous studies have indicated that the main molecular characteristic of aging is the progressive accumulation of oxidative damages in cellular macromolecules. Proteins are one of the main molecular targets of age-related oxidative stress, which have been observed during aging process in cellular systems. Reactive oxygen species (ROS) can lead to oxidation of amino acid side chains, formation of protein-protein cross-linkages, and oxidation of the peptide backbones. In the present study, we report the age-dependent oxidative alterations in biomarkers of plasma protein oxidation: protein carbonyls (PCO), advanced oxidation protein products (AOPPs) and plasma total thiol groups (T-SH) in the Indian population and also correlate these parameters with total plasma antioxidant potential. We show an age dependent decrease in T-SH levels and increase in PCO and AOPPs level. The alterations in the levels of these parameters correlated significantly with the total antioxidant capacity of the plasma. The levels of oxidized proteins in plasma provide an excellent biomarker of oxidative stress due to the relative long half-life of such oxidized proteins. PMID:20826915

Serum uric acid is not independently associated with plasma renin activity and plasma aldosterone in hypertensive adults.

PubMed

Mulè, G; Castiglia, A; Morreale, M; Geraci, G; Cusumano, C; Guarino, L; Altieri, D; Panzica, M; Vaccaro, F; Cottone, S

2017-04-01

In experimental investigations conducted in rats, raising serum uric acid (SUA) levels resulted in the stimulation of intrarenal renin expression. Studies in humans exploring the association of SUA with plasma renin activity (PRA) yielded conflicting results. Moreover, little is known about the relationship of SUA with plasma aldosterone concentration (PAC). The study aimed to assess the relationship between SUA levels, PRA, and PAC and the influence of age, gender, body mass index (BMI), and hyperuricemia on these relationships in subjects with essential hypertension (EH). We enrolled 372 hypertensive patients (mean age 45 ± 12 years, men 67%) with uncomplicated EH that was not pharmacologically treated. The study population was divided in tertiles according to SUA levels. While PRA did not differ significantly across the three tertiles, PAC was higher in subjects belonging to the uppermost tertile of SUA than those in the lower ones (p = 0.0429); however, this difference lost statistical significance after adjustment for age, sex, BMI, and serum creatinine. Univariate correlation analyses showed significant associations of SUA with PRA (r = 0.137; p = 0.008) and PAC (r = 0.179; p < 0.001). However, these relationships were not significant after correcting for confounding factors in multiple linear regression analyses. We did not observe statistically significant effect modification by gender, age, BMI, and hyperuricemia. SUA levels are weakly associated with PRA and PAC in adults with untreated EH. These relationships were lost after adjustment for age, sex, BMI, and serum creatinine. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Glomerular Hyperfiltration in Adult Sickle Cell Anemia: A Frequent Hemolysis Associated Feature

PubMed Central

Stankovic, Katia; Levy, Pierre; Avellino, Virginie; Tharaux, Pierre-Louis; Letavernier, Emmanuel; Grateau, Gilles; Baud, Laurent; Girot, Robert; Lionnet, François

2010-01-01

Background and objectives: Sickle cell anemia-associated nephropathy is a growing matter of concern because renal failure affects most aging sickle cell anemia patients. Glomerular damage is a common feature revealed by a microalbuminuria or a macroalbuminuria. Although glomerular hyperfiltration has been described for decades in this population, its prevalence in young adults is unknown. Design, setting, participants, & measurements: To address this issue, as well as the clinical and biologic correlates of hyperfiltration, a single-center, cross-sectional study of 280 homozygous SS disease patients was performed. Results: The prevalence of hyperfiltration assessed by Modification of Diet in Renal Disease estimated GFR was 51%. Among patients with hyperfiltration, 49% had hyperfiltration alone, whereas 36% and 15% had an associated microalbuminuria or macroalbuminuria, respectively. Estimated GFR sensitivity and specificity for hyperfiltration were 94% and 63%, respectively, in a selected subgroup of 48 patients (measured GFR was assessed by urinary 51Cr EDTA clearance). In patients with no albuminuria, hyperfiltration status was significantly associated with a young age (years), the absence of alpha thalassemia, a lower hemoglobin level (g/dl), and a lower fetal hemoglobin. The role of chronic hemolysis was further strengthened by multivariate analysis showing a correlation between estimated GFR and a low plasma fetal hemoglobin level, a young age, and a high reticulocyte count (r2 = 0.54). Conclusions: Together, the data suggest that the pathophysiology of hyperfiltration would rather be attributable to the hemolysis-associated vasculopathy rather than a viscosity-vaso-occlusive process. PMID:20185605

T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate.

PubMed

Ise, Wataru; Fujii, Kentaro; Shiroguchi, Katsuyuki; Ito, Ayako; Kometani, Kohei; Takeda, Kiyoshi; Kawakami, Eiryo; Yamashita, Kazuo; Suzuki, Kazuhiro; Okada, Takaharu; Kurosaki, Tomohiro

2018-04-17

Higher- or lower-affinity germinal center (GC) B cells are directed either to plasma cell or GC recycling, respectively; however, how commitment to the plasma cell fate takes place is unclear. We found that a population of light zone (LZ) GC cells, Bcl6 lo CD69 hi expressing a transcription factor IRF4 and higher-affinity B cell receptors (BCRs) or Bcl6 hi CD69 hi with lower-affinity BCRs, favored the plasma cell or recycling GC cell fate, respectively. Mechanistically, CD40 acted as a dose-dependent regulator for Bcl6 lo CD69 hi cell formation. Furthermore, we found that expression of intercellular adhesion molecule 1 (ICAM-1) and signaling lymphocytic activation molecule (SLAM) in Bcl6 lo CD69 hi cells was higher than in Bcl6 hi CD69 hi cells, thereby affording more stable T follicular helper (Tfh)-GC B cell contacts. These data support a model whereby commitment to the plasma cell begins in the GC and suggest that stability of Tfh-GC B cell contacts is key for plasma cell-prone GC cell formation. Copyright © 2018. Published by Elsevier Inc.

Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh.

PubMed

Aktar, Amena; Rahman, M Arifur; Afrin, Sadia; Akter, Aklima; Uddin, Taher; Yasmin, Tahirah; Sami, Md Israk Nur; Dash, Pinki; Jahan, Sultana Rownok; Chowdhury, Fahima; Khan, Ashraful I; LaRocque, Regina C; Charles, Richelle C; Bhuiyan, Taufiqur Rahman; Mandlik, Anjali; Kelly, Meagan; Kováč, Pavol; Xu, Peng; Calderwood, Stephen B; Harris, Jason B; Qadri, Firdausi; Ryan, Edward T

2018-04-01

The mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection. In this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2). The presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses. These results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1.

Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh

PubMed Central

Aktar, Amena; Rahman, M. Arifur; Afrin, Sadia; Akter, Aklima; Uddin, Taher; Yasmin, Tahirah; Sami, Md. Israk Nur; Dash, Pinki; Jahan, Sultana Rownok; Chowdhury, Fahima; Khan, Ashraful I.; LaRocque, Regina C.; Charles, Richelle C.; Bhuiyan, Taufiqur Rahman; Mandlik, Anjali; Kelly, Meagan; Kováč, Pavol; Xu, Peng; Calderwood, Stephen B.; Harris, Jason B.; Ryan, Edward T.

2018-01-01

Background The mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection. Methodology In this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2). Principle findings The presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses. Conclusion These results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1. PMID:29684006

No strict requirement for eosinophils for bone marrow plasma cell survival.

PubMed

Bortnick, Alexandra; Chernova, Irene; Spencer, Sean P; Allman, David

2018-02-14

Lasting antibody responses are maintained by long-lived plasma cells, which are thought to lodge in the BM in specialized survival niches. Eosinophils have been reported to function as a critical component of the BM survival niche where they are thought to provide pro-survival signals to nearby plasma cells. Recent study shows that many BM plasma cells are recently generated and chiefly short-lived cells, raising the possibility that rare plasma cell-eosinophil interactions are a rate-limiting step needed to establish lasting humoral immunity. To address these issues, we examined the impact of eosinophil depletion on short- and long-lived BM plasma cells in the context of antibody responses induced by both T-cell dependent and T-cell independent antigens. Surprisingly, our results failed to support a role for eosinophils in either plasma cell generation or survival. These studies included examination of plasma cell frequencies in mice lacking eosinophils either after antibody-mediated depletion, or due to mutation of the GATA1 locus. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Testosterone in human studies: Modest associations between plasma and salivary measurements.

PubMed

de Wit, A E; Bosker, F J; Giltay, E J; de Kloet, C S; Roelofs, K; van Pelt, J; Penninx, B W J H; Schoevers, R A

2018-02-01

Testosterone is involved in many processes like aggression and mood disorders. As it may easily diffuse from blood into saliva, salivary testosterone is thought to reflect plasma free testosterone level. If so, it would provide a welcome noninvasive and less stressful alternative to blood sampling. Past research did not reveal consensus regarding the strength of the association, but sample sizes were small. This study aimed to analyse the association in a large cohort. In total, 2,048 participants (age range 18-65 years; 696 males and 1,352 females) were included and saliva (using cotton Salivettes) and plasma were collected for testosterone measurements. Levels were determined by enzyme-linked immunosorbent assay and radioimmunoassay respectively. Free testosterone was calculated by the Vermeulen algorithm. Associations were determined using linear regression analyses. Plasma total and free testosterone showed a significant association with salivary testosterone in men (adjusted β = .09, p = .01; and β = .15, p < .001, respectively) and in women (adjusted β = .08, p = .004; and crude β = .09, p = .002 respectively). The modest associations indicate that there are many influencing factors of both technical and biological origin. © 2017 Blackwell Verlag GmbH.

Ageing mechanisms and associated lipid changes.

PubMed

Kolovou, Genovefa; Katsiki, Niki; Pavlidis, Antonis; Bilianou, Helen; Goumas, George; Mikhailidis, Dimitri P

2014-01-01

Ageing is related to slowdown/breakdown of the somatotropic axis (i.e. the somatopause) leading to many physiological changes. The somatopause is accompanied by DNA and other macromolecule damage, and is characterized by a progressive decline in vitality and tissue function. We still do not have a definitive understanding of the mechanism( s) of ageing. Several overlapping theories have been proposed such as: 1) The free radical theory, 2) Mitochondrial Ageing, 3) The Glycation Theory, 4) Protein Damage and Maintenance in Ageing, and, 5) DNA Damage and Repair. Furthermore, several models of ageing were introduced such as genetically programmed senescence, telomere shortening, genomic instability, heterochromatin loss, altered epigenetic patterns and long lived cells. There are certain lipid modifications associated with the somatopause, characterized mainly by an increase in total cholesterol and triglyceride levels in both genders. In this review we consider the mechanisms of ageing and the associated changes in lipid metabolism according to gender.

Age- and Sex-associated Differences in Phenotypic and Functional Characteristics of Peripheral Blood Lymphocytes in Chimpanzees (Pan troglodytes).

PubMed

Nehete, Pramod N; Magden, Elizabeth R; Nehete, Bharti P; Williams, Lawrence E; Abee, Christian R; Sastry, K Jagannadha

2017-09-01

Chimpanzees are the closest phylogenetic relatives to humans, sharing more than 98% genetic sequence identity. These genetic similarities prompted the belief that chimpanzees can serve as an ideal model for human disease conditions and vaccine development. However, in light of the recent NIH decision to phase out biomedical research in chimpanzees and retire NIH-supported chimpanzees, data from the present study will continue to provide value for the care of aged and sick chimpanzees located in zoos, sanctuaries, and primate centers. Surprisingly little information has been published regarding the normal chimpanzee immune system, and most extant studies have been based on small numbers of animals. In the current study, we provide a better understanding of the chimpanzee immune system with regard to age and sex. We examined immune parameters of chimpanzees (n = 94; 51 female, 43 male; age, 6 to 47 y) by using flow cytometry, immune function analysis, and cytokine analysis. Because lymphocytes are key mediators of cellular immune responses, particularly to intracellular pathogens such as viruses, we surveyed the phenotypic and functional attributes of T and B lymphocytes in this healthy and age-stratified population of chimpanzees. We noted a significantly higher percentage of CD16+T cells in male compared with female chimpanzees but no significant changes in percentages of CD3+, CD4+, CD8+, or CD4+CD8+ T cells with age or sex. In addition, aging was associated with decreased proliferative responses to mitogens in both sexes. Sex-specific differences also were present in the percentage of NK cells but not in their cytotoxic activity and in circulating cytokine levels in plasma. Going forward, the data presented here regarding immune cell changes associated with aging in healthy chimpanzees will serve to enhance the care of geriatric and ill animals.

Novel ageing-biomarker discovery using data-intensive technologies.

PubMed

Griffiths, H R; Augustyniak, E M; Bennett, S J; Debacq-Chainiaux, F; Dunston, C R; Kristensen, P; Melchjorsen, C J; Navarrete, Santos A; Simm, A; Toussaint, O

2015-11-01

Ageing is accompanied by many visible characteristics. Other biological and physiological markers are also well-described e.g. loss of circulating sex hormones and increased inflammatory cytokines. Biomarkers for healthy ageing studies are presently predicated on existing knowledge of ageing traits. The increasing availability of data-intensive methods enables deep-analysis of biological samples for novel biomarkers. We have adopted two discrete approaches in MARK-AGE Work Package 7 for biomarker discovery; (1) microarray analyses and/or proteomics in cell systems e.g. endothelial progenitor cells or T cell ageing including a stress model; and (2) investigation of cellular material and plasma directly from tightly-defined proband subsets of different ages using proteomic, transcriptomic and miR array. The first approach provided longitudinal insight into endothelial progenitor and T cell ageing. This review describes the strategy and use of hypothesis-free, data-intensive approaches to explore cellular proteins, miR, mRNA and plasma proteins as healthy ageing biomarkers, using ageing models and directly within samples from adults of different ages. It considers the challenges associated with integrating multiple models and pilot studies as rational biomarkers for a large cohort study. From this approach, a number of high-throughput methods were developed to evaluate novel, putative biomarkers of ageing in the MARK-AGE cohort. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

Alpha-synuclein levels in blood plasma decline with healthy aging.

PubMed

Koehler, Niklas K U; Stransky, Elke; Meyer, Mirjam; Gaertner, Susanne; Shing, Mona; Schnaidt, Martina; Celej, Maria S; Jovin, Thomas M; Leyhe, Thomas; Laske, Christoph; Batra, Anil; Buchkremer, Gerhard; Fallgatter, Andreas J; Wernet, Dorothee; Richartz-Salzburger, Elke

2015-01-01

There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years) compared to younger (avg. 27.6 years) individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001), possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.

Low Temperature Plasma for the Treatment of Epithelial Cancer Cells

NASA Astrophysics Data System (ADS)

Mohades, Soheila

Biomedical applications of low temperature plasmas (LTP) may lead to a paradigm shift in treating various diseases by conducting fundamental research on the effects of LTP on cells, tissues, organisms (plants, insects, and microorganisms). This is a rapidly growing interdisciplinary research field that involves engineering, physics, life sciences, and chemistry to find novel solutions for urgent medical needs. Effects of different LTP sources have shown the anti-tumor properties of plasma exposure; however, there are still many unknowns about the interaction of plasma with eukaryotic cells which must be elucidated in order to evaluate the practical potential of plasma in cancer treatment. Plasma, the fourth state of matter, is composed of electrons, ions, reactive molecules (radicals and non-radicals), excited species, radiation, and heat. A sufficient dose (time) of plasma exposure can induce death in cancer cells. The plasma pencil is employed to study the anti-tumor properties of this treatment on epithelial cells. The plasma pencil has been previously used for the inactivation of bacteria, destroying amyloid fibrils, and the killing of various cancer cells. Bladder cancer is the 9th leading cause of cancer. In this dissertation, human urinary bladder tissue with the squamous cell carcinoma disease (SCaBER cells) is treated with LTP utilizing two different approaches: direct plasma exposure and Plasma Activated Media (PAM) as an advancement to the treatment. PAM is produced by exposing a liquid cell culture medium to the plasma pencil. Direct LTP treatment of cancer cells indicates a dose-dependent killing effect at post-treatment times. Similarly, PAM treatment shows an anti-cancer effect by inducing substantial cell death. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have an important role in the biomedical effects of LTP treatment. This study demonstrates the capability of the plasma pencil to transport ROS/RNS into cell culture media

Proximity to a Major Road and Plasma Cytokines in School-Aged Children.

PubMed

Rosser, Franziska; Forno, Erick; Brehm, John; Han, Yueh-Ying; Boutaoui, Nadia; Colón-Semidey, Angel; Alvarez, María; Acosta-Pérez, Edna; Kurland, Kristen S; Alcorn, John F; Canino, Glorisa; Celedón, Juan C

2016-09-01

Traffic-related air pollution (TRAP) may affect immune responses, including those in the T H 2 and T H 17 pathways. To examine whether TRAP is associated with plasma level of T H 17-, T H 1-, and T H 2-related cytokines in children with and without asthma, a cross-sectional study of 577 children (ages 6-14 years) with ( n  = 294) and without ( n  = 283) asthma in San Juan (Puerto Rico) was performed. Residential distance to a major road was estimated using geocoded home addresses for study participants. A panel of 14 cytokines, enriched for the T H 17 pathway, was measured in plasma. Asthma was defined as physician-diagnosed asthma and current wheeze. Multivariable linear regression was used to examine the association of residential distance to a major road (a marker of TRAP), asthma, and cytokine levels. Among all participating children, residential proximity to a major road was significantly associated with increased plasma level of IL-31, even after adjustment for relevant covariates and correction for multiple testing. The presence of asthma modified the estimated effect of the residential distance to a major road on plasma TNF-α ( P for interaction = 0.00047). Although living farther from a major road was significantly associated with lower TNF-α level in control subjects, no such decrease was seen in children with asthma. In a direct comparison of cases and control subjects, children with asthma had significantly higher levels of IL-1β, IL-22, and IL-33 than control subjects. TRAP is associated with increased levels of proinflammatory cytokines among Puerto Rican children, who belong to an ethnic group with high risk for asthma.

Occurrence of fibronectin-fibrin complexes in plasma of patients with multimorbidity due to the inflamm-aging phenomenon.

PubMed

Pupek, Małgorzata; Pawłowicz, Robert; Lindner, Karolina; Krzyżanowska-Gołąb, Dorota; Lemańska-Perek, Anna; Panaszek, Bernard; Kątnik-Prastowska, Iwona

2016-05-01

Multimorbidity is the co-occurrence of chronic diseases associated with low-grade chronic inflammation of connective tissue. Frequency of occurrence and relative amounts of fibronectin (FN) complexes with fibrin (FN-fibrin) and FN monomer were analyzed in 130 plasma samples of 18 to 94-year-old multimorbid patients in relation to concentrations of FN and extra domain A (EDA)-FN, and C-reactive protein (CRP) as well as to age, number of coexisting chronic diseases and presence of specified diseases. Immunoblotting revealed, besides FN dimer, the presence of FN monomer, and 750-, 1000-, and 1300-kDa FN-fibrin complexes in the multimorbid plasmas. The FN-fibrin complexes appeared more frequently and in higher relative amounts, but FN monomer less frequently and in a lower relative amount in the groups of elderly multimorbid patients, with a higher number of coexisting diseases and with dominance of cardiovascular diseases and osteoarthrosis, and with CRP concentration of 3-5mg/l. In contrast, the normal plasma contained only the FN-fibrin complex of 750 kDa in a lower relative amount, but with an increasing amount with normal aging. Moreover, FN concentration increased and EDA-FN decreased with the number of co-existing diseases and aging of patients, although both concentration values were lower than in the age-matched normal groups. FN concentration was the lowest in the exacerbation of a chronic disease and EDA-FN in the stable chronic disease groups. The alterations in plasma FN molecular status were associated with micro-inflammation and micro-coagulation, as well as multimorbidity of subjects and their physiological aging. Copyright © 2016 Elsevier Inc. All rights reserved.

ER-to-plasma membrane tethering proteins regulate cell signaling and ER morphology.

PubMed

Manford, Andrew G; Stefan, Christopher J; Yuan, Helen L; Macgurn, Jason A; Emr, Scott D

2012-12-11

Endoplasmic reticulum-plasma membrane (ER-PM) junctions are conserved structures defined as regions of the ER that tightly associate with the plasma membrane. However, little is known about the mechanisms that tether these organelles together and why such connections are maintained. Using a quantitative proteomic approach, we identified three families of ER-PM tethering proteins in yeast: Ist2 (related to mammalian TMEM16 ion channels), the tricalbins (Tcb1/2/3, orthologs of the extended synaptotagmins), and Scs2 and Scs22 (vesicle-associated membrane protein-associated proteins). Loss of all six tethering proteins results in the separation of the ER from the PM and the accumulation of cytoplasmic ER. Importantly, we find that phosphoinositide signaling is misregulated at the PM, and the unfolded protein response is constitutively activated in the ER in cells lacking ER-PM tether proteins. These results reveal critical roles for ER-PM contacts in cell signaling, organelle morphology, and ER function. Copyright © 2012 Elsevier Inc. All rights reserved.

The influence of surface properties of plasma-etched polydimethylsiloxane (PDMS) on cell growth and morphology.

PubMed

Pennisi, Cristian P; Zachar, Vladimir; Gurevich, Leonid; Patriciu, Andrei; Struijk, Johannes J

2010-01-01

Polydimethylsiloxane (PDMS) or silicone rubber is a widely used implant material. Approaches to promote tissue integration to PDMS are desirable to avoid clinical problems associated with sliding and friction between tissue and implant. Plasma-etching is a useful way to control cell behavior on PDMS without additional coatings. In this work, different plasma processing conditions were used to modify the surface properties of PDMS substrates. Surface nanotopography and wettability were measured to study their effect on in vitro growth and morphology of fibroblasts. While fluorinated plasma treatments produced nanorough hydrophobic and superhydrophobic surfaces that had negative or little influences on cellular behavior, water vapor/oxygen plasma produced smooth hydrophillic surfaces that enhanced cell growth.

The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated Damage

PubMed Central

Costa, Barbara; Cavallini, Chiara; Testai, Lara; Martelli, Alma; Calderone, Vincenzo; Martini, Claudia

2017-01-01

In recent years, the health-promoting effects of the citrus flavanone naringenin have been examined. The results have provided evidence for the modulation of some key mechanisms involved in cellular damage by this compound. In particular, naringenin has been revealed to have protective properties such as an antioxidant effect in cardiometabolic disorders. Very recently, beneficial effects of naringenin have been demonstrated in old rats. Because aging has been demonstrated to be directly related to the occurrence of cardiac disorders, in the present study, the ability of naringenin to prevent cardiac cell senescence was investigated. For this purpose, a cellular model of senescent myocardial cells was set up and evaluated using colorimetric, fluorimetric, and immunometric techniques. Relevant cellular senescence markers, such as X-gal staining, cell cycle regulator levels, and the percentage of cell cycle-arrested cells, were found to be reduced in the presence of naringenin. In addition, cardiac markers of aging-induced damage, including radical oxidative species levels, mitochondrial metabolic activity, mitochondrial calcium buffer capacity, and estrogenic signaling functions, were also modulated by the compound. These results suggested that naringenin has antiaging effects on myocardial cells. PMID:28386313

Haloperidol and reduced haloperidol concentrations in plasma and red blood cells from chronic schizophrenic patients.

PubMed

Ko, G N; Korpi, E R; Kirch, D G

1989-06-01

In a double-blind, placebo-controlled study, 15 drug-free chronic schizophrenic inpatients were treated with a fixed dose of haloperidol for 6 weeks. Haloperidol and its metabolite, reduced haloperidol, were measured in plasma and red blood cells after 2, 4, and 6 weeks of treatment. Behavioral change was rated using the Brief Psychiatric Rating Scale (BPRS). Not only the raw concentrations, but also blood compartment sums and ratios of these four drug measurements were tested for their strength of association with behavioral improvement. Positive associations with some BPRS subscales at some time points emerged; however, no significant correlations were found to extend across all time points measured. There was a trend in this cohort for negative symptom improvement to be associated with the ratio of haloperidol to reduced haloperidol in red blood cells. The ratio of haloperidol to reduced haloperidol in plasma was always greater than that in the red blood cells for all patients, reflecting an accumulation of the metabolite in red blood cells.

Cold atmospheric plasma treatment inhibits growth in colorectal cancer cells.

PubMed

Schneider, Christin; Arndt, Stephanie; Zimmermann, Julia L; Li, Yangfang; Karrer, Sigrid; Bosserhoff, Anja-Katrin

2018-06-01

Plasma oncology is a relatively new field of research. Recent developments have indicated that cold atmospheric plasma (CAP) technology is an interesting new therapeutic approach to cancer treatment. In this study, p53 wildtype (LoVo) and human p53 mutated (HT29 and SW480) colorectal cancer cells were treated with the miniFlatPlaSter - a device particularly developed for the treatment of tumor cells - that uses the Surface Micro Discharge (SMD) technology for plasma production in air. The present study analyzed the effects of plasma on colorectal cancer cells in vitro and on normal colon tissue ex vivo. Plasma treatment had strong effects on colon cancer cells, such as inhibition of cell proliferation, induction of cell death, and modulation of p21 expression. In contrast, CAP treatment of murine colon tissue ex vivo for up to 2 min did not show any toxic effect on normal colon cells compared to H2O2 positive control. In summary, these results suggest that the miniFlatPlaSter plasma device is able to kill colorectal cancer cells independent of their p53 mutation status. Thus, this device presents a promising new approach in colon cancer therapy.

The sirtuin family's role in aging and age-associated pathologies.

PubMed

Hall, Jessica A; Dominy, John E; Lee, Yoonjin; Puigserver, Pere

2013-03-01

The 7 mammalian sirtuin proteins compose a protective cavalry of enzymes that can be invoked by cells to aid in the defense against a vast array of stressors. The pathologies associated with aging, such as metabolic syndrome, neurodegeneration, and cancer, are either caused by or exacerbated by a lifetime of chronic stress. As such, the activation of sirtuin proteins could provide a therapeutic approach to buffer against chronic stress and ameliorate age-related decline. Here we review experimental evidence both for and against this proposal, as well as the implications that isoform-specific sirtuin activation may have for healthy aging in humans.

High folic acid intake reduces natural killer cell cytotoxicity in aged mice

USDA-ARS?s Scientific Manuscript database

Presence of unmetabolized folic acid in plasma, which is indicative of folic acid intake beyond the metabolic capacity of the body, is associated with reduced natural killer (NK) cell cytotoxicity in post-menopausal women >/= 50 years. NK cells are cytotoxic lymphocytes that are part of the innate i...

Higher Plasma Phospholipid n–3 PUFAs, but Lower n–6 PUFAs, Are Associated with Lower Pulse Wave Velocity among Older Adults123

PubMed Central

Reinders, Ilse; Murphy, Rachel A; Song, Xiaoling; Mitchell, Gary F; Visser, Marjolein; Cotch, Mary Frances; Garcia, Melissa E; Launer, Lenore J; Eiriksdottir, Gudny; Gudnason, Vilmundur; Harris, Tamara B; Brouwer, Ingeborg A

2015-01-01

Background: Higher intake of polyunsaturated fatty acids (PUFAs) and higher circulating PUFAs are associated with lower cardiovascular disease (CVD) risk. The positive influence of PUFAs might be via lowering arterial stiffness, resulting in a better CVD risk profile; however, studies investigating circulating PUFAs in relation to arterial stiffness in a general population are limited. Objective: We investigated the associations of plasma phospholipid n–3 (ω-3) and n–6 PUFAs and fish oil intake with arterial stiffness. Methods: We used data from a subgroup of the Age, Gene/Environment Susceptibility–Reykjavik (AGES-Reykjavik) Study (n = 501, 75.0 ± 4.96 y, 46% men), a population-based study of community-dwelling older adults. Plasma phospholipid PUFAs were measured by GC at baseline, and fish oil intake was assessed at 3 time points: early life (ages 14–19 y), midlife (ages 40–50 y), and late life (ages 66–96 y, AGES-Reykjavik baseline) with the use of a validated food-frequency questionnaire. Arterial stiffness was determined as carotid–femoral pulse wave velocity (cf-PWV) with the use of an electrocardiogram after a mean follow-up of 5.2 ± 0.3 y. Regression coefficients (95% CIs), adjusted for demographics, follow-up time, risk factors, cholesterol, triglycerides, and serum vitamin D, were calculated by linear regression per SD increment in PUFAs. Results: Plasma total n–3 PUFAs, eicosapentaenoic acid, and docosahexaenoic acid were associated with lower cf-PWV [β (95% CI): −0.036 (−0.064, −0.008); −0.031 (−0.059, −0.003); −0.036 (−0.064, −0.009), respectively]. In contrast, plasma total n–6 PUFAs and linoleic acid were associated with higher cf-PWV [0.035 (0.009, 0.061) and 0.034 (0.008, 0.059)]. Regular fish oil consumption at early-, mid-, and late-life was not associated with cf-PWV. Conclusions: Our results show a positive association between plasma n–6 PUFAs and arterial stiffness, and suggest that higher

Systematization of the Mechanism by Which Plasma Irradiation Causes Cell Growth and Tumor Cell Death

NASA Astrophysics Data System (ADS)

Shimizu, Nobuyuki

2015-09-01

New methods and technologies have improved minimally invasive surgical treatment and saved numerous patients. Recently, plasma irradiation has been demonstrated that might be useful in medical field and the plasma irradiation device is expected to become practically applicable. Mild plasma coagulator showed some advantages such as hemostasis and adhesion reduction in experimental animal model, but the mechanism of plasma irradiation remains unclear. Our study group aim to clarify the mechanism of plasma irradiation effects, mainly focusing on oxidative stress using cultured cell lines and small animal model. First, a study using cultured cell lines showed that the culture medium that was activated by plasma irradiation (we called this kind of medium as ``PAM'' -plasma activated medium-) induced tumor cell death. Although this effect was mainly found to be due to hydrogen peroxide, the remaining portion was considered as the specific effect of the plasma irradiation and we are now studying focusing on this effect. Second, we established a mouse intra-peritoneal adhesion model and checked biological reaction that occurred in the adhesion part. Histopathological study showed inflammatory cells infiltration into adhesion part and the expression of PTX3 that might involve tissue repair around adhesion part. We also confirmed that cytokines IL-6 and IL-10 might be useful as a marker of adhesion formation in this model. Applying ``PAM'' or mild plasma irradiation in this model, we examine the effects of plasma on inflamed cells. The samples in these experiments would be applied to targeted proteomics analysis, and we aim to demonstrate the systematization of the cell's reaction by plasma irradiation.

Physical activity opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes plasma endothelin-1 levels in individuals with essential hypertension.

PubMed

Nyberg, M; Mortensen, S P; Hellsten, Y

2013-03-01

Endothelin-1 has potent constrictor and proliferative activity in vascular smooth muscle, and essential hypertension and aging are associated with increased endothelin-1-mediated vasoconstrictor tone. The aim of this study was to investigate the effect of physical activity, hypertension and age on endothelin-1 levels in plasma and skeletal muscle and endothelin receptors in skeletal muscle in human subjects. In study 1, normotensive (46 ± 1 years, n = 11) and hypertensive (47 ± 1 years, n = 10) subjects were studied before and after 8 weeks of aerobic exercise training. In study 2, young (23 ± 1 years, n = 8), older lifelong sedentary (66 ± 2 years, n = 8) and older lifelong endurance-trained (62 ± 2 years, n = 8) subjects were studied in a cross-sectional design. Skeletal muscle and plasma endothelin-1 levels were increased with age and plasma endothelin-1 levels were higher in hypertensive than normotensive individuals. Eight weeks of exercise training normalized plasma endothelin-1 levels in the hypertensive subjects and increased the protein expression of the ET(A) receptor in skeletal muscle of normotensive subjects. Similarly, individuals that had performed lifelong physical activity had similar plasma and muscle endothelin-1 levels as the young controls and had higher ET(A) receptor levels. Our findings suggest that aerobic exercise training opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes plasma endothelin-1 levels in individuals with essential hypertension. This effect may explain some of the beneficial effects of training on the cardiovascular system in older and hypertensive subjects. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.

Clearance of autophagy-associated dying retinal pigment epithelial cells – a possible source for inflammation in age-related macular degeneration

PubMed Central

Szatmári-Tóth, M; Kristóf, E; Veréb, Z; Akhtar, S; Facskó, A; Fésüs, L; Kauppinen, A; Kaarniranta, K; Petrovski, G

2016-01-01

Retinal pigment epithelial (RPE) cells can undergo different forms of cell death, including autophagy-associated cell death during age-related macular degeneration (AMD). Failure of macrophages or dendritic cells (DCs) to engulf the different dying cells in the retina may result in the accumulation of debris and progression of AMD. ARPE-19 and primary human RPE cells undergo autophagy-associated cell death upon serum depletion and oxidative stress induced by hydrogen peroxide (H2O2). Autophagy was revealed by elevated light-chain-3 II (LC3-II) expression and electron microscopy, while autophagic flux was confirmed by blocking the autophago-lysosomal fusion using chloroquine (CQ) in these cells. The autophagy-associated dying RPE cells were engulfed by human macrophages, DCs and living RPE cells in an increasing and time-dependent manner. Inhibition of autophagy by 3-methyladenine (3-MA) decreased the engulfment of the autophagy-associated dying cells by macrophages, whereas sorting out the GFP-LC3-positive/autophagic cell population or treatment by the glucocorticoid triamcinolone (TC) enhanced it. Increased amounts of IL-6 and IL-8 were released when autophagy-associated dying RPEs were engulfed by macrophages. Our data suggest that cells undergoing autophagy-associated cell death engage in clearance mechanisms guided by professional and non-professional phagocytes, which is accompanied by inflammation as part of an in vitro modeling of AMD pathogenesis. PMID:27607582

Vitamin D Deficiency in Community-Dwelling Elderly Is Not Associated with Age-Related Macular Degeneration.

PubMed

Cougnard-Grégoire, Audrey; Merle, Bénédicte M J; Korobelnik, Jean-Francois; Rougier, Marie-Bénédicte; Delyfer, Marie-Noëlle; Féart, Catherine; Le Goff, Mélanie; Dartigues, Jean-François; Barberger-Gateau, Pascale; Delcourt, Cécile

2015-08-01

Elderly persons are at elevated risk of vitamin D deficiency, which is involved in various health problems. However, its relation with age-related macular degeneration (AMD) is debated. We investigated factors associated with plasma 25-hydroxyvitamin D [25(OH)D] deficiency and the associations between plasma 25(OH)D concentrations and AMD in elderly subjects. Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes (ALIENOR) is a population-based study on eye diseases performed in elderly residents of Bordeaux, France. Plasma 25(OH)D concentrations were assessed from blood samples and categorized as <25 nmol/L (deficiency), 25-49 nmol/L (insufficiency), or ≥50 nmol/L (sufficiency). AMD was classified as: no AMD, early AMD, and late AMD. Associations between baseline characteristics and plasma 25(OH)D status were examined with multinomial logistic regression analysis. Associations between AMD and plasma 25(OH)D status were estimated using generalized estimating equation logistic regressions. Six hundred ninety-seven subjects with complete data were included. The prevalence of plasma 25(OH)D deficiency and insufficiency were 27.3% and 55.9%, respectively. In multivariate analysis, 25(OH)D deficiency was significantly associated with older age (P = 0.0007), females (P = 0.0007), absence of physical activity (P = 0.01), absence of vitamin D supplementation (P < 0.0001), higher plasma total cholesterol (P = 0.007), use of fibrates (P < 0.0001), lower alcohol consumption (P = 0.02), and season of blood sampling (P < 0.0001). After adjustment for these covariates and dietary omega-3 polyunsaturated fatty acid intake, smoking, and body mass index, no significant associations were found between early AMD and 25(OH)D insufficiency or deficiency (OR: 0.71, P = 0.12; OR: 0.73, P = 0.23, respectively) or with late AMD (OR: 1.04, P = 0.93; OR: 0.74, P = 0.59, respectively). These findings underline the very high prevalence of plasma 25(OH)D deficiency in this elderly

Increased Arf/p53 activity in stem cells, aging and cancer.

PubMed

Carrasco-Garcia, Estefania; Moreno, Manuel; Moreno-Cugnon, Leire; Matheu, Ander

2017-04-01

Arf/p53 pathway protects the cells against DNA damage induced by acute stress. This characteristic is the responsible for its tumor suppressor activity. Moreover, it regulates the chronic type of stress associated with aging. This is the basis of its anti-aging activity. Indeed, increased gene dosage of Arf/p53 displays elongated longevity and delayed aging. At a cellular level, it has been recently shown that increased dosage of Arf/p53 delays age-associated stem cell exhaustion and the subsequent decline in tissue homeostasis and regeneration. However, p53 can also promote aging if constitutively activated. In this context, p53 reduces tissue regeneration, which correlates with premature exhaustion of stem cells. We discuss here the current evidence linking the Arf/p53 pathway to the processes of aging and cancer through stem cell regulation. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism.

PubMed

Obeid, Rima; Awwad, Hussain M; Rabagny, Yannick; Graeber, Stefan; Herrmann, Wolfgang; Geisel, Juergen

2016-03-01

Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment. We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans. A total of 283 individuals (mean ± SD age: 66.7 ± 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured. Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 μmol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM), and higher percentages of men and subjects with diabetes. The difference in plasma TMAO concentrations between men and women (7.3 ± 10.0 compared with 5.4 ± 5.6 μmol/L, respectively) was NS after adjustment for age and creatinine (P = 0.455). The TMAO:trimethylamine ratio was higher in men (P < 0.001). Diabetes was associated with significantly higher plasma TMAO concentration (8.6 ± 12.2 compared with 5.4 ± 5.2 μmol/L) even after adjustments. Sex and diabetes showed an interactive effect on trimethylamine concentrations (P = 0.010) but not on TMAO concentrations (P = 0.950). Positive determinants of TMAO in a stepwise regression model that applied to the whole group were SAH, trimethylamine, choline, and female sex, whereas plasma phosphatidylcholine was a negative determinant. High TMAO and choline concentrations are associated with an advanced cardiometabolic risk profile. Diabetes is related to higher plasma TMAO

A two-dimensional particle-in-cell model of a dusty plasma

NASA Technical Reports Server (NTRS)

Young, B.; Cravens, T. E.; Armstrong, T. P.; Friauf, R. J.

1994-01-01

Dusty plasmas are present in comets, in the ring systems of the outer planets, and in the interstellar medium. A two-dimensional particle-in-cell (PIC) model of a dusty plasma is presented in this paper. The PIC code is best suited for modeling the plasma-dust interaction for large grains, with diameters of the order of a centimeter. We have modeled the charging process for an individual dust grain and the associated potential pattern in the surrounding plasma. We have also considered the case of a large number of grains in a plasma, with intergrain separations of the order of the Debye length, and have shown that the plasma becomes depleted and the charge on a dust grain is reduced, as other workers in this field have predicted (cf. C. K. Goertz, 1989). We examine the electron and ion distribution functions in the vicinity of a charged grain and demonstrate that the ions near a grain have clearly been accelerated by the electrostatic potential.

Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer

PubMed Central

Adams, Peter D.; Jasper, Heinrich; Rudolph, K. Lenhard

2015-01-01

Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here we discuss possible explanations for age-associated increases in the initiation and/or progression of mutant stem/progenitor clones and highlight the roles of stem cell quiescence, replication-associated DNA damage, telomere shortening, epigenetic alterations, and metabolic challenges as determinants of stem cell mutations and clonal dominance in aging. PMID:26046760

Red blood cell transfusion is associated with further bleeding and fresh-frozen plasma with mortality in nonvariceal upper gastrointestinal bleeding.

PubMed

Subramaniam, Kavitha; Spilsbury, Katrina; Ayonrinde, Oyekoya T; Latchmiah, Faye; Mukhtar, Syed A; Semmens, James B; Leahy, Michael F; Olynyk, John K

2016-04-01

Blood products are commonly transfused for patients with nonvariceal upper gastrointestinal bleeding (NVUGIB). While concerns exist about further bleeding and mortality in subsets of patients receiving red blood cell (RBC) transfusion, the impact of non-RBC blood products has not previously been systematically investigated. The aim of the study was to investigate the associations between blood products transfusion, further bleeding, and mortality after acute NVUGIB. A retrospective cohort study examined further bleeding and 30-day and 1-year mortality in adult patients who underwent gastroscopy for suspected acute NVUGIB between 2008 and 2010 in three tertiary hospitals in Western Australia. Survival analysis was performed. A total of 2228 adults (63% male) with 2360 hospital admissions for NVUGIB met the inclusion criteria. Median age at presentation was 70 years (range, 19-99 years). Thirty-day mortality was 4.9% and 1-year mortality was 13.9%. Transfusion of 4 or more units of RBCs was associated with greater than 10 times the odds of further bleeding in patients with a hemoglobin level of more than 90 g/L (odds ratio, 11.9; 95% confidence interval [CI], 3.1-45.7; p ≤ 0.001), but was not associated with mortality. Administration of 5 or more units of fresh-frozen plasma (FFP) was associated with increased 30-day (hazard ratio, 2.8; 95% CI, 1.3-5.9; p = 0.008) and 1-year (hazard ratio, 2.6; 95% CI, 1.3-5.0; p = 0.005) mortality after adjusting for coagulopathy, comorbidity, Rockall score, and other covariates. In this large, multicenter study of NVUGIB, RBC transfusion was associated with further bleeding but not mortality, while FFP transfusion was associated with increased mortality in a subset of patients. © 2015 AABB.

Centrosome and microtubule instability in aging Drosophila cells

NASA Technical Reports Server (NTRS)

Schatten, H.; Chakrabarti, A.; Hedrick, J.

1999-01-01

Several cytoskeletal changes are associated with aging which includes alterations in muscle structure leading to muscular atrophy, and weakening of the microtubule network which affects cellular secretion and maintenance of cell shape. Weakening of the microtubule network during meiosis in aging oocytes can result in aneuploidy or trisomic zygotes with increasing maternal age. Imbalances of cytoskeletal organization can lead to disease such as Alzheimer's, muscular disorders, and cancer. Because many cytoskeletal diseases are related to age we investigated the effects of aging on microtubule organization in cell cultures of the Drosophila cell model system (Schneider S-1 and Kc23 cell lines). This cell model is increasingly being used as an alternative system to mammalian cell cultures. Drosophila cells are amenable to genetic manipulations and can be used to identify and manipulate genes which are involved in the aging processes. Immunofluorescence, scanning, and transmission electron microscopy were employed for the analysis of microtubule organizing centers (centrosomes) and microtubules at various times after subculturing cells in fresh medium. Our results reveal that centrosomes and the microtubule network becomes significantly affected in aging cells after 5 days of subculture. At 5-14 days of subculture, 1% abnormal out of 3% mitoses were noted which were clearly distinguishable from freshly subcultured control cells in which 3% of cells undergo normal mitosis with bipolar configurations. Microtubules are also affected in the midbody during cell division. The midbody in aging cells becomes up to 10 times longer when compared with midbodies in freshly subcultured cells. During interphase, microtubules are often disrupted and disorganized, which may indicate improper function related to transport of cell organelles along microtubules. These results are likely to help explain some cytoskeletal disorders and diseases related to aging.

Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging.

PubMed

Xiong, Yuyan; Yepuri, Gautham; Necetin, Sevil; Montani, Jean-Pierre; Ming, Xiu-Fen; Yang, Zhihong

2017-06-01

Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L -arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II -/- ) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II -/- ) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice. © 2017 by the American Diabetes Association.

Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

PubMed

Uryga, Anna K; Bennett, Martin R

2016-04-15

Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Long-term exposure to air pollution is associated with biological aging

PubMed Central

Ward-Caviness, Cavin K.; Nwanaji-Enwerem, Jamaji C.; Wolf, Kathrin; Wahl, Simone; Colicino, Elena; Trevisi, Letizia; Kloog, Itai; Just, Allan C.; Vokonas, Pantel; Cyrys, Josef; Gieger, Christian; Schwartz, Joel; Baccarelli, Andrea A.; Schneider, Alexandra; Peters, Annette

2016-01-01

Long-term exposure to air pollution is associated with age-related diseases. We explored the association between accelerated biological aging and air pollution, a potential mechanism linking air pollution and health. We estimated long-term exposure to PM10, PM2.5, PM2.5 absorbance/black carbon (BC), and NOx via land-use regression models in individuals from the KORA F4 cohort. Accelerated biological aging was assessed using telomere length (TeloAA) and three epigenetic measures: DNA methylation age acceleration (DNAmAA), extrinsic epigenetic age acceleration (correlated with immune cell counts, EEAA), and intrinsic epigenetic age acceleration (independent of immune cell counts, IEAA). We also investigated sex-specific associations between air pollution and biological aging, given the published association between sex and aging measures. In KORA an interquartile range (0.97 μg/m3) increase in PM2.5 was associated with a 0.33 y increase in EEAA (CI = 0.01, 0.64; P = 0.04). BC and NOx (indicators or traffic exposure) were associated with DNAmAA and IEAA in women, while TeloAA was inversely associated with BC in men. We replicated this inverse BC-TeloAA association in the Normative Aging Study, a male cohort based in the USA. A multiple phenotype analysis in KORA F4 combining all aging measures showed that BC and PM10 were broadly associated with biological aging in men. Thus, we conclude that long-term exposure to air pollution is associated with biological aging measures, potentially in a sex-specific manner. However, many of the associations were relatively weak and further replication of overall and sex-specific associations is warranted. PMID:27793020

Long-term exposure to air pollution is associated with biological aging.

PubMed

Ward-Caviness, Cavin K; Nwanaji-Enwerem, Jamaji C; Wolf, Kathrin; Wahl, Simone; Colicino, Elena; Trevisi, Letizia; Kloog, Itai; Just, Allan C; Vokonas, Pantel; Cyrys, Josef; Gieger, Christian; Schwartz, Joel; Baccarelli, Andrea A; Schneider, Alexandra; Peters, Annette

2016-11-15

Long-term exposure to air pollution is associated with age-related diseases. We explored the association between accelerated biological aging and air pollution, a potential mechanism linking air pollution and health. We estimated long-term exposure to PM10, PM2.5, PM2.5 absorbance/black carbon (BC), and NOx via land-use regression models in individuals from the KORA F4 cohort. Accelerated biological aging was assessed using telomere length (TeloAA) and three epigenetic measures: DNA methylation age acceleration (DNAmAA), extrinsic epigenetic age acceleration (correlated with immune cell counts, EEAA), and intrinsic epigenetic age acceleration (independent of immune cell counts, IEAA). We also investigated sex-specific associations between air pollution and biological aging, given the published association between sex and aging measures. In KORA an interquartile range (0.97 µg/m3) increase in PM2.5 was associated with a 0.33 y increase in EEAA (CI = 0.01, 0.64; P = 0.04). BC and NOx (indicators or traffic exposure) were associated with DNAmAA and IEAA in women, while TeloAA was inversely associated with BC in men. We replicated this inverse BC-TeloAA association in the Normative Aging Study, a male cohort based in the USA. A multiple phenotype analysis in KORA F4 combining all aging measures showed that BC and PM10 were broadly associated with biological aging in men. Thus, we conclude that long-term exposure to air pollution is associated with biological aging measures, potentially in a sex-specific manner. However, many of the associations were relatively weak and further replication of overall and sex-specific associations is warranted.

Association of plasma Aß peptides with blood pressure in the elderly.

PubMed

Lambert, Jean-Charles; Dallongeville, Jean; Ellis, Kathryn A; Schraen-Maschke, Susanna; Lui, James; Laws, Simon; Dumont, Julie; Richard, Florence; Cottel, Dominique; Berr, Claudine; Ames, David; Masters, Colin L; Rowe, Christopher C; Szoeke, Cassandra; Tzourio, Christophe; Dartigues, Jean-François; Buée, Luc; Martins, Ralph; Amouyel, Philippe

2011-04-15

Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion. We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively). Plasma Aß(1-40) and Aß(1-42) levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß(1-42)/ Aß(1-40) ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß(1-42)/Aß(1-40) ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß(1-42)/ Aß(1-40) ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37-0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß(1-40). The plasma Aß(1-42)/Aß(1-40) ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimer's disease, in which a high Aß(1-42)/Aß(1-40) plasma ratio is reportedly associated with a decreased risk of incident disease.

Seminal plasma induces global transcriptomic changes associated with cell migration, proliferation and viability in endometrial epithelial cells and stromal fibroblasts

PubMed Central

Chen, Joseph C.; Johnson, Brittni A.; Erikson, David W.; Piltonen, Terhi T.; Barragan, Fatima; Chu, Simon; Kohgadai, Nargis; Irwin, Juan C.; Greene, Warner C.; Giudice, Linda C.; Roan, Nadia R.

2014-01-01

STUDY QUESTION How does seminal plasma (SP) affect the transcriptome of human primary endometrial epithelial cells (eEC) and stromal fibroblasts (eSF)? SUMMARY ANSWER Exposure of eEC and eSF to SP in vitro increases expression of genes and secreted proteins associated with cellular migration, proliferation, viability and inhibition of cell death. WHAT IS KNOWN ALREADY Studies in both humans and animals suggest that SP can access and induce physiological changes in the upper female reproductive tract (FRT), which may participate in promoting reproductive success. STUDY DESIGN, SIZE, DURATION This is a cross sectional study involving control samples versus treatment. SP (pooled from twenty donors) was first tested for dose- and time-dependent cytotoxic effects on eEC and eSF (n = 4). As exposure of eEC or eSF to 1% SP for 6 h proved to be non-toxic, a second set of eEC/eSF samples (n = 4) was treated under these conditions for transcriptome, protein and functional analysis. With a third set of samples (n = 3), we further compared the transcriptional response of the cells to SP versus fresh semen. PARTICIPANTS/MATERIALS, SETTING, METHODS eEC and eSF were isolated from endometrial biopsies from women of reproductive age undergoing benign gynecologic procedures and maintained in vitro. RNA was isolated and processed for microarray studies to analyze global transcriptomic changes. Secreted factors in conditioned media from SP-treated cells were analyzed by Luminex and for the ability to stimulate migration of CD14+ monocytes and CD4+ T cells. MAIN RESULTS AND THE ROLE OF CHANCE Pathway identifications were determined using the Z-scoring system in Ingenuity Pathways Analysis (Z scores ≥|1.5|). SP induced transcriptomic changes (P < 0.05) associated with promoting leukocyte and endothelial cell recruitment, and proliferation of eEC and eSF. Cell viability pathways were induced, while those associated with cell death were suppressed (P < 0.05). SP and fresh semen induced

Apoptosis in capillary endothelial cells in ageing skeletal muscle

PubMed Central

Wang, Huijuan; Listrat, Anne; Meunier, Bruno; Gueugneau, Marine; Coudy-Gandilhon, Cécile; Combaret, Lydie; Taillandier, Daniel; Polge, Cécile; Attaix, Didier; Lethias, Claire; Lee, Kijoon; Goh, Kheng Lim; Béchet, Daniel

2014-01-01

The age-related loss of skeletal muscle mass and function (sarcopenia) is a consistent hallmark of ageing. Apoptosis plays an important role in muscle atrophy, and the intent of this study was to specify whether apoptosis is restricted to myofibre nuclei (myonuclei) or occurs in satellite cells or stromal cells of extracellular matrix (ECM). Sarcopenia in mouse gastrocnemius muscle was characterized by myofibre atrophy, oxidative type grouping, delocalization of myonuclei and ECM fibrosis. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) indicated a sharp rise in apoptosis during ageing. TUNEL coupled with immunostaining for dystrophin, paired box protein-7 (Pax7) or laminin-2α, respectively, was used to identify apoptosis in myonuclei, satellite cells and stromal cells. In adult muscle, apoptosis was not detected in myofibres, but was restricted to stromal cells. Moreover, the age-related rise in apoptotic nuclei was essentially due to stromal cells. Myofibre-associated apoptosis nevertheless occurred in old muscle, but represented < 20% of the total muscle apoptosis. Specifically, apoptosis in old muscle affected a small proportion (0.8%) of the myonuclei, but a large part (46%) of the Pax7+ satellite cells. TUNEL coupled with CD31 immunostaining further attributed stromal apoptosis to capillary endothelial cells. Age-dependent rise in apoptotic capillary endothelial cells was concomitant with altered levels of key angiogenic regulators, perlecan and a perlecan domain V (endorepellin) proteolytic product. Collectively, our results indicate that sarcopenia is associated with apoptosis of satellite cells and impairment of capillary functions, which is likely to contribute to the decline in muscle mass and functionality during ageing. PMID:24245531

Age exacerbates HIV-associated white matter abnormalities.

PubMed

Seider, Talia R; Gongvatana, Assawin; Woods, Adam J; Chen, Huaihou; Porges, Eric C; Cummings, Tiffany; Correia, Stephen; Tashima, Karen; Cohen, Ronald A

2016-04-01

Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV-) individuals aged 23-79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV- participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV-associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.

Primary Plasma Cell Leukemia Associated with t(6;14)(p21;q32) and IGH Rearrangement: A Case Study and Review of the Literature.

PubMed

Cho, Sun Young; Lim, Gayoung; Oh, Seung Hwan; Lee, Hee Joo; Suh, Jin-Tae; Lee, Juhie; Lee, Woo-In; Lee, Hong Ghi; Yoon, Hwi-Joong; Park, Tae Sung

2011-01-01

Because plasma cell leukemia (PCL) is a rare and distinct variant among plasma cell dyscrasias, recent clinical and cytogenetic studies have been performed in different ethnic groups to define the characteristics of these PCL patients. As far as we know, IGH rearrangements involving t(11;14) and (14;16) are significantly more frequent in PCL than in myeloma patients. However, PCL cases associated with t(6;14)(p21;q32) or IGH-CCND3 rearrangement are extremely rare in the literature; only one PCL case with t(6;14) has been documented. A 61-year-old female was admitted due to fatigue, weight loss, and exertional dyspnea. Plasmacytoid cells were counted up to 76% at a peripheral blood film, but bone marrow aspiration failed because of dry-tapping. Flow cytometric analysis showed positive for CD138 and cytoplasmic kappa light chain. Chromosome analysis revealed t(6;14)(p21;q32), which was confirmed by an IGH split-out probe in FISH analysis. Immunofixation electrophoresis also presented monoclonal bands identified as IgG and kappa light chain. Finally, she was diagnosed as primary PCL associated with t(6;14) and IGH rearrangement. Although considerable advances have been made in the understanding of the biology and molecular pathogenesis of PCL, further clinical, laboratory, and genetic studies of PCL associated with such a rare IGH rearrangement would be necessary in the future. To the best of our knowledge, this is the first report of PCL associated with t(6;14) as a sole chromosomal abnormality.

Basic Research in Plasma Medicine - A Throughput Approach from Liquids to Cells

PubMed Central

Bekeschus, Sander; Schmidt, Anke; Niessner, Felix; Gerling, Torsten; Weltmann, Klaus-Dieter; Wende, Kristian

2017-01-01

In plasma medicine, ionized gases with temperatures close to that of vertebrate systems are applied to cells and tissues. Cold plasmas generate reactive species known to redox regulate biological processes in health and disease. Pre-clinical and clinical evidence points to beneficial effects of plasma treatment in the healing of chronic ulcer of the skin. Other emerging topics, such as plasma cancer treatment, are receiving increasing attention. Plasma medical research requires interdisciplinary expertise in physics, chemistry, and biomedicine. One goal of plasma research is to characterize plasma-treated cells in a variety of specific applications. This includes, for example, cell count and viability, cellular oxidation, mitochondrial activity, cytotoxicity and mode of cell death, cell cycle analysis, cell surface marker expression, and cytokine release. This study describes the essential equipment and workflows required for such research in plasma biomedicine. It describes the proper operation of an atmospheric pressure argon plasma jet, specifically monitoring its basic emission spectra and feed gas settings to modulate reactive species output. Using a high-precision xyz-table and computer software, the jet is hovered in millisecond-precision over the cavities of 96-well plates in micrometer-precision for maximal reproducibility. Downstream assays for liquid analysis of redox-active molecules are shown, and target cells are plasma-treated. Specifically, melanoma cells are analyzed in an efficient sequence of different consecutive assays but using the same cells: measurement of metabolic activity, total cell area, and surface marker expression of calreticulin, a molecule important for the immunogenic cell death of cancer cells. These assays retrieve content-rich biological information about plasma effects from a single plate. Altogether, this study describes the essential steps and protocols for plasma medical research. PMID:29286412

Basic Research in Plasma Medicine - A Throughput Approach from Liquids to Cells.

PubMed

Bekeschus, Sander; Schmidt, Anke; Niessner, Felix; Gerling, Torsten; Weltmann, Klaus-Dieter; Wende, Kristian

2017-11-17

In plasma medicine, ionized gases with temperatures close to that of vertebrate systems are applied to cells and tissues. Cold plasmas generate reactive species known to redox regulate biological processes in health and disease. Pre-clinical and clinical evidence points to beneficial effects of plasma treatment in the healing of chronic ulcer of the skin. Other emerging topics, such as plasma cancer treatment, are receiving increasing attention. Plasma medical research requires interdisciplinary expertise in physics, chemistry, and biomedicine. One goal of plasma research is to characterize plasma-treated cells in a variety of specific applications. This includes, for example, cell count and viability, cellular oxidation, mitochondrial activity, cytotoxicity and mode of cell death, cell cycle analysis, cell surface marker expression, and cytokine release. This study describes the essential equipment and workflows required for such research in plasma biomedicine. It describes the proper operation of an atmospheric pressure argon plasma jet, specifically monitoring its basic emission spectra and feed gas settings to modulate reactive species output. Using a high-precision xyz-table and computer software, the jet is hovered in millisecond-precision over the cavities of 96-well plates in micrometer-precision for maximal reproducibility. Downstream assays for liquid analysis of redox-active molecules are shown, and target cells are plasma-treated. Specifically, melanoma cells are analyzed in an efficient sequence of different consecutive assays but using the same cells: measurement of metabolic activity, total cell area, and surface marker expression of calreticulin, a molecule important for the immunogenic cell death of cancer cells. These assays retrieve content-rich biological information about plasma effects from a single plate. Altogether, this study describes the essential steps and protocols for plasma medical research.

The plasma membrane recycling pathway and cell polarity in plants: studies on PIN proteins.

PubMed

Boutté, Yohann; Crosnier, Marie-Thérèse; Carraro, Nicola; Traas, Jan; Satiat-Jeunemaitre, Béatrice

2006-04-01

The PIN-FORMED (PIN) proteins are plasma-membrane-associated facilitators of auxin transport. They are often targeted to one side of the cell only through subcellular mechanisms that remain largely unknown. Here, we have studied the potential roles of the cytoskeleton and endomembrane system in the localisation of PIN proteins. Immunocytochemistry and image analysis on root cells from Arabidopsis thaliana and maize showed that 10-30% of the intracellular PIN proteins mapped to the Golgi network, but never to prevacuolar compartments. The remaining 70-90% were associated with yet to be identified structures. The maintenance of PIN proteins at the plasma membrane depends on a BFA-sensitive machinery, but not on microtubules and actin filaments. The polar localisation of PIN proteins at the plasmamembrane was not reflected by any asymmetric distribution of cytoplasmic organelles. In addition, PIN proteins were inserted in a symmetrical manner at both sides of the cell plate during cytokinesis. Together, the data indicate that the localisation of PIN proteins is a postmitotic event, which depends on local characteristics of the plasma membrane and its direct environment. In this context, we present evidence that microtubule arrays might define essential positional information for PIN localisation. This information seems to require the presence of an intact cell wall.

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)—Patient Version

Cancer.gov

Plasma cell neoplasms occur when abnormal plasma cells or myeloma cells form tumors in the bones or soft tissues of the body. Multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma, and monoclonal gammopathy of undetermined significance (MGUS) are different types of plasma cell neoplasms. Find out about risk factors, symptoms, diagnostic tests, prognosis, and treatment for these diseases.

Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

PubMed

Schwörer, Simon; Becker, Friedrich; Feller, Christian; Baig, Ali H; Köber, Ute; Henze, Henriette; Kraus, Johann M; Xin, Beibei; Lechel, André; Lipka, Daniel B; Varghese, Christy S; Schmidt, Manuel; Rohs, Remo; Aebersold, Ruedi; Medina, Kay L; Kestler, Hans A; Neri, Francesco; von Maltzahn, Julia; Tümpel, Stefan; Rudolph, K Lenhard

2016-12-15

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFβ, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice.

PubMed

Singh, Kameshwar P; Bennett, John A; Casado, Fanny L; Walrath, Jason L; Welle, Stephen L; Gasiewicz, Thomas A

2014-01-15

Loss of immune function and increased hematopoietic disease are among the most clinically significant consequences of aging. Hematopoietic stem cells (HSCs) from mice lacking aryl hydrocarbon receptor (AhR) have high rates of cell division. Studies were designed to test the hypothesis that aging AhR-null allele (AhR-KO) mice develop premature HSC exhaustion, and changes leading to hematological disease. Compared to wild-type, aging AhR-KO mice showed a decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, and anemia. Analysis of bone marrow indicated increased numbers of stem/progenitor and lineage-committed cells, but decreased erythroid progenitors. There was also decreased self-renewal capacity of HSCs determined by competitive repopulation and serial transplantation. HSCs also showed increased levels of reactive oxygen species (ROS), Ki-67, and γ-H2A.X, but decreased p16(Ink4a). Splenic cells from aging KO mice had abnormal expression of genes, including Gata-1, Sh2d3c, Gfi-1, p21, and c-myc, involved in trafficking and associated with leukemia. HSCs from AhR-KO mice had gene changes related to HSC maintenance and consistent with phenotype observed. The most prominent gene changes (overexpression of Srpk2, Creb1, Hes1, mtor, pdp1) have been associated with HSC hyperproliferation, leukemia, and accelerated aging. Pathway analyses also indicated an enrichment of genes associated with oxidative stress, acute myelogenous leukemia, aging, and heat shock response, and the β-catenin/Wnt pathways. These data indicate that loss of AhR and associated changes in multiple signaling pathways promote premature HSC exhaustion and development of a myeloproliferative disorder. They also implicate a critical role of the AhR in the regulation of HSCs.

Simultaneous occurrence of a CD30 positive/ALK-negative high grade T-cell lymphoma and plasma cell myeloma: Report of a case.

PubMed

Nassif, Samer; El-Majzoub, Nadim; Abbas, Ossama; Temraz, Sally; Chakhachiro, Zaher

2015-03-01

Simultaneous occurrences of T-cell and B-cell neoplasms are rare, and etiological relationships between these two malignancies are poorly understood. We report the case of a 76-year-old man who presented with hypercalcemia, multiple skin nodular lesions, fatigue, episodic fever, and night sweats. PET/CT scan showed diffuse skin and subcutaneous fat plane active lesions, supra- and infra- diaphragmatic active lymph nodes, liver and spleen involvement, bone marrow infiltration, and nonspecific bilateral lung nodules. A skin biopsy showed a high grade CD30-positive/ALK-negative T-cell lymphoma. A bone marrow biopsy showed involvement by the same neoplastic cells. Additionally, a monoclonal lambda restricted plasma cell population (15% of marrow elements) was identified, which, in view of an IgA lambda spike in the serum, was consistent with plasma cell myeloma. To the best of our knowledge, this case is the first reported case of a plasma cell neoplasm associated with an aggressive CD30-positive ALK-negative systemic T-cell lymphoma with skin involvement. Reporting such cases is important as it adds to the pool of rare cases of concomitant T-cell neoplasms and plasma cell myelomas, and might help in determining an etiological relationship, if any, between these two hematological malignancies. Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Metabolic enzymes in glial cells of the honeybee brain and their associations with aging, starvation and food response.

PubMed

Shah, Ashish K; Kreibich, Claus D; Amdam, Gro V; Münch, Daniel

2018-01-01

The honey bee has been extensively studied as a model for neuronal circuit and memory function and more recently has emerged as an unconventional model in biogerontology. Yet, the detailed knowledge of neuronal processing in the honey bee brain contrasts with the very sparse information available on glial cells. In other systems glial cells are involved in nutritional homeostasis, detoxification, and aging. These glial functions have been linked to metabolic enzymes, such as glutamine synthetase and glycogen phosphorylase. As a step in identifying functional roles and potential differences among honey bee glial types, we examined the spatial distribution of these enzymes and asked if enzyme abundance is associated with aging and other processes essential for survival. Using immunohistochemistry and confocal laser microscopy we demonstrate that glutamine synthetase and glycogen phosphorylase are abundant in glia but appear to co-localize with different glial sub-types. The overall spatial distribution of both enzymes was not homogenous and differed markedly between different neuropiles and also within each neuropil. Using semi-quantitative Western blotting we found that rapid aging, typically observed in shortest-lived worker bees (foragers), was associated with declining enzyme levels. Further, we found enzyme abundance changes after severe starvation stress, and that glutamine synthetase is associated with food response. Together, our data indicate that aging and nutritional physiology in bees are linked to glial specific metabolic enzymes. Enzyme specific localization patterns suggest a functional differentiation among identified glial types.

Leydig Cell Aging and Hypogonadism

PubMed Central

Beattie, M.C.; Adekola, L.; Papadopoulos, V.; Chen, H.; Zirkin, B.R.

2015-01-01

Leydig cell testosterone (T) production is reduced with age, resulting in reduced serum T levels (hypogonadism). A number of cellular changes have been identified in the steroidogenic pathway of aged Leydig cells that are associated with reduced T formation, including reductions in luteinizing hormone (LH)-stimulated cAMP production, the cholesterol transport proteins steroidogenic acute regulatory (STAR) protein and translocator protein (TSPO), and downstream steroidogenic enzymes of the mitochondria and smooth endoplasmic reticulum. Many of the changes in steroid formation that characterize aged Leydig cells can be elicited by the experimental alteration of the redox environment of young cells, suggesting that changes in the intracellular redox balance may cause reduced T production. Hypogonadism is estimated to affect about 5 million American men, including both aged and young. This condition has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction. Exogenous T administration is now used widely to elevate serum T levels in hypogonadal men and thus to treat symptoms of hypogonadism. However, recent evidence suggests that men who take exogenous T may face increased risk of stroke, heart attack, and prostate tumorigenesis. Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig cell T production, reduced intratesticular T concentration, and reduced spermatogenesis. This makes exogenous T administration inappropriate for men who wish to father children. There are promising new approaches to increase serum T by directly stimulating Leydig cell T production rather than by exogenous T therapy, thus potentially avoiding some of its negative consequences. PMID:25700847

Leydig cell aging and hypogonadism.

PubMed

Beattie, M C; Adekola, L; Papadopoulos, V; Chen, H; Zirkin, B R

2015-08-01

Leydig cell testosterone (T) production is reduced with age, resulting in reduced serum T levels (hypogonadism). A number of cellular changes have been identified in the steroidogenic pathway of aged Leydig cells that are associated with reduced T formation, including reductions in luteinizing hormone (LH)-stimulated cAMP production, the cholesterol transport proteins steroidogenic acute regulatory (STAR) protein and translocator protein (TSPO), and downstream steroidogenic enzymes of the mitochondria and smooth endoplasmic reticulum. Many of the changes in steroid formation that characterize aged Leydig cells can be elicited by the experimental alteration of the redox environment of young cells, suggesting that changes in the intracellular redox balance may cause reduced T production. Hypogonadism is estimated to affect about 5 million American men, including both aged and young. This condition has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction. Exogenous T administration is now used widely to elevate serum T levels in hypogonadal men and thus to treat symptoms of hypogonadism. However, recent evidence suggests that men who take exogenous T may face increased risk of stroke, heart attack, and prostate tumorigenesis. Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig cell T production, reduced intratesticular T concentration, and reduced spermatogenesis. This makes exogenous T administration inappropriate for men who wish to father children. There are promising new approaches to increase serum T by directly stimulating Leydig cell T production rather than by exogenous T therapy, thus potentially avoiding some of its negative consequences. Copyright © 2015 Elsevier Inc. All rights reserved.

Phase imaging microscopy for the diagnostics of plasma-cell interaction

NASA Astrophysics Data System (ADS)

Ohene, Yolanda; Marinov, Ilya; de Laulanié, Lucie; Dupuy, Corinne; Wattelier, Benoit; Starikovskaia, Svetlana

2015-06-01

Phase images of biological specimens were obtained by the method of Quadriwave Lateral Shearing Interferometry (QWLSI). The QWLSI technique produces, at high resolution, phase images of the cells having been exposed to a plasma treatment and enables the quantitative analysis of the changes in the surface area of the cells over time. Morphological changes in the HTori normal thyroid cells were demonstrated using this method. There was a comparison of the cell behaviour between control cells, cells treated by plasma of a nanosecond dielectric barrier discharge, including cells pre-treated by catalase, and cells treated with an equivalent amount of H2O2. The major changes in the cell membrane morphology were observed at only 5 min after the plasma treatment. The primary role of reactive oxygen species (ROS) in this degradation is suggested. Deformation and condensation of the cell nucleus were observed 2-3 h after the treatment and are supposedly related to apoptosis induction. The coupling of the phase QWLSI with immunofluorescence imaging would give a deeper insight into the mechanisms of plasma induced cell death.

Plasma cell cheilitis, successfully treated with topical 0.03% tacrolimus ointment.

PubMed

Jin, Seon Pil; Cho, Kwang Hyun; Huh, Chang Hun

2010-05-01

Plasma cell cheilitis is a rare, idiopathic mucosal condition. The treatment of plasma cell cheilitis is often disappointing. It is often resistant to various topical treatments. We present a 65-year-old woman who had a painful, eroded area on her lower lip, which responded poorly to various topical treatments. A biopsy revealed a band-like infiltration composed mainly of plasma cells in the dermis. She was diagnosed as having plasma cell cheilitis, and was successfully treated with 0.03% topical tacrolimus ointment.

Cardiorespiratory fitness modifies the association between dietary fat intake and plasma fatty acids.

PubMed

König, D; Väisänen, S B; Bouchard, C; Halle, M; Lakka, T A; Baumstark, M W; Alen, M; Berg, A; Rauramaa, R

2003-07-01

To investigate the relation between (1) cardiorespiratory fitness and plasma saturated, monounsaturated and polyunsaturated fatty acids and (2) the interactions between cardiorespiratory fitness, dietary fat intake and plasma fatty acid composition. Cross-sectional analysis. The subjects were randomly selected, 127 middle-aged Finnish men participating in the DNASCO exercise intervention study. Cardiorespiratory fitness was determined spiroergometrically, dietary intake of macro- and micronutrients by 4-day food records and plasma fatty acids by gas chromatography. The subjects were divided into tertiles of aerobic fitness. Differences between fitness tertiles were not observed for dietary intake of total fat, and saturated, monounsaturated or polyunsaturated fatty acids (percent of total energy). In contrast, plasma saturated fatty acids were significantly lower (P <0.01) and polyunsaturated fatty acids significantly higher (P <0.05) in the highest fitness tertile compared to the lowest tertile. Dietary saturated fat intake was positively associated with plasma saturated fatty acids (r=0.342; P <0.05) and inversely with plasma polyunsaturated fatty acids (r=-0.453; P <0.01) only in the lowest fitness tertile. In addition, a positive correlation between body mass index and plasma saturated fatty acids (r=0.516; P <0.01) as well as a negative correlation between body mass index and plasma polyunsaturated fatty acids (r=-0.516; P <0.01) was observed in the lowest tertile solely. Different levels in cardiorespiratory fitness are associated with different levels in plasma saturated and polyunsaturated fatty acids and lead to modifications in the association between dietary and plasma fatty acids. These findings can perhaps be explained by a reduced hepatic fatty acid and lipoprotein synthesis as well as by an enhanced muscular lipid utilization, which are commonly seen in those who are physically active and who exhibit a higher level of fitness.

Plasma long-chain omega-3 polyunsaturated fatty acids and macular pigment in subjects with family history of age-related macular degeneration: the Limpia Study.

PubMed

Merle, Bénédicte M J; Buaud, Benjamin; Korobelnik, Jean-François; Bron, Alain; Delyfer, Marie-Noëlle; Rougier, Marie-Bénédicte; Savel, Hélène; Vaysse, Carole; Creuzot-Garcher, Catherine; Delcourt, Cécile

2017-12-01

In numerous epidemiological studies, omega-3 polyunsaturated fatty acids (PUFAs) have been associated with a decreased risk of age-related macular degeneration (AMD). Beyond their structural, functional and neuroprotective roles, omega-3 PUFAs may favour the retinal accumulation of lutein and zeaxanthin and thus increase macular pigment optical density (MPOD). We examined the associations of MPOD with plasma omega-3 PUFAs in subjects with family history of AMD. The Limpia study is a double-blind, placebo-controlled, prospective randomized clinical trial performed in 120 subjects. Subjects with at least one parent treated for neovascular AMD, aged 40-70, with a best corrected visual acuity (BCVA) >20/25, free of late AMD and other major eye conditions and with no use of supplement containing lutein or zeaxanthin the preceding year were recruited in Bordeaux and Dijon, France. At baseline, MPOD within 1° of eccentricity was measured by modified Heidelberg retinal analyser (Heidelberg, Germany) and plasma omega-3 PUFAs by gas chromatography. Medical history and lifestyle data were collected from a standardized questionnaire. Associations of MPOD with plasma omega-3 PUFAs were assessed at the baseline examination, using mixed linear models adjusted for age, gender, centre, body mass index, smoking, plasma high-density lipoprotein (HDL) cholesterol and lutein+zeaxanthin. After multivariate adjustment, high MPOD was significantly associated with higher level of plasma docosapentaenoic acid (DPA) (β = 0.029, 95% CI: 0.003, 0.055; p = 0.03). Plasma alpha linolenic, eicosapentaenoic and docosahexaenoic acids were not significantly associated with MPOD. In the Limpia study, high MPOD within 1° was significantly associated with higher plasma levels of omega-3 DPA. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Successful treatment of plasma cell cheilitis with topical tacrolimus: report of two cases.

PubMed

Hanami, Yuka; Motoki, Yoshikazu; Yamamoto, Toshiyuki

2011-02-15

Plasma cell cheilitis is an uncommon chronic inflammatory dermatitis that presents with flat to slightly elevated erosive erythematous plaques. It is histologically characterized by plasma cell infiltrates into the mucosa. Other than the lip, genital areas are often involved, which is called plasma cell balanitis or vulvitis. Plasma cell cheilitis is sometimes resistant to conventional topical corticosteroid therapy. Other choices include oral griseofulvin, topical cyclosporine, and intralesional corticosteroid injection, all of which occasionally fail to produce satisfactory results. Recent reports show that topical calcineurin inhibitors are effective for plasma cell cheilitis, balanitis, and vulvitis. However, there are so far only 2 reports of plasma cell cheilitis successfully treated with topical pimecrolimus and tacrolimus. We present herein two cases of plasma cell cheilitis, in which topical tacrolimus showed beneficial effects, suggesting that this immunomodulatory agent is a promising option for plasma cell cheilitis.

MAMP (microbe-associated molecular pattern)-induced changes in plasma membrane-associated proteins.

PubMed

Uhlíková, Hana; Solanský, Martin; Hrdinová, Vendula; Šedo, Ondrej; Kašparovský, Tomáš; Hejátko, Jan; Lochman, Jan

2017-03-01

Plant plasma membrane associated proteins play significant roles in Microbe-Associated Molecular Pattern (MAMP) mediated defence responses including signal transduction, membrane transport or energetic metabolism. To elucidate the dynamics of proteins associated with plasma membrane in response to cryptogein, a well-known MAMP of defence reaction secreted by the oomycete Phytophthora cryptogea, 2D-Blue Native/SDS gel electrophoresis of plasma membrane fractions was employed. This approach revealed 21 up- or down-regulated protein spots of which 15 were successfully identified as proteins related to transport through plasma membrane, vesicle trafficking, and metabolic enzymes including cytosolic NADP-malic enzyme and glutamine synthetase. Observed changes in proteins were also confirmed on transcriptional level by qRT-PCR analysis. In addition, a significantly decreased accumulation of transcripts observed after employment of a mutant variant of cryptogein Leu41Phe, exhibiting a conspicuous defect in induction of resistance, sustains the contribution of identified proteins in cryptogein-triggered cellular responses. Our data provide further evidence for dynamic MAMP-induced changes in plasma membrane associated proteins. Copyright © 2016 Elsevier GmbH. All rights reserved.

New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes

PubMed Central

Jiang, Chao; Krzyzanowski, Gary D.; Ryan, Wayne L.

2017-01-01

Cell-free DNA (cfDNA) in blood is used as a source of genetic material for noninvasive prenatal and cancer diagnostic assays in clinical practice. Recently we have started a project for new biomarker discovery with a view to developing new noninvasive diagnostic assays. While reviewing literature, it was found that exosomes may be a rich source of biomarkers, because exosomes play an important role in human health and disease. While characterizing exosomes found in human blood plasma, we observed the presence of cfDNA in plasma exosomes. Plasma was obtained from blood drawn into K3EDTA tubes. Exosomes were isolated from cell-free plasma using a commercially available kit. Sizing and enumeration of exosomes were done using electron microscopy and NanoSight particle counter. NanoSight and confocal microscopy was used to demonstrate the association between dsDNA and exosomes. DNA extracted from plasma and exosomes was measured by a fluorometric method and a droplet digital PCR (ddPCR) method. Size of extracellular vesicles isolated from plasma was heterogeneous and showed a mean value of 92.6 nm and a mode 39.7 nm. A large proportion of extracellular vesicles isolated from plasma were identified as exosomes using a fluorescence probe specific for exosomes and three protein markers, Hsp70, CD9 and CD63, that are commonly used to identify exosome fraction. Fluorescence dye that stain dsDNA showed the association between exosomes and dsDNA. Plasma cfDNA concentration analysis showed more than 93% of amplifiable cfDNA in plasma is located in plasma exosomes. Storage of a blood sample showed significant increases in exosome count and exosome DNA concentration. This study provide evidence that a large proportion of plasma cfDNA is localized in exosomes. Exosome release from cells is a metabolic energy dependent process, thus suggesting active release of cfDNA from cells as a source of cfDNA in plasma. PMID:28850588

New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes.

PubMed

Fernando, M Rohan; Jiang, Chao; Krzyzanowski, Gary D; Ryan, Wayne L

2017-01-01

Cell-free DNA (cfDNA) in blood is used as a source of genetic material for noninvasive prenatal and cancer diagnostic assays in clinical practice. Recently we have started a project for new biomarker discovery with a view to developing new noninvasive diagnostic assays. While reviewing literature, it was found that exosomes may be a rich source of biomarkers, because exosomes play an important role in human health and disease. While characterizing exosomes found in human blood plasma, we observed the presence of cfDNA in plasma exosomes. Plasma was obtained from blood drawn into K3EDTA tubes. Exosomes were isolated from cell-free plasma using a commercially available kit. Sizing and enumeration of exosomes were done using electron microscopy and NanoSight particle counter. NanoSight and confocal microscopy was used to demonstrate the association between dsDNA and exosomes. DNA extracted from plasma and exosomes was measured by a fluorometric method and a droplet digital PCR (ddPCR) method. Size of extracellular vesicles isolated from plasma was heterogeneous and showed a mean value of 92.6 nm and a mode 39.7 nm. A large proportion of extracellular vesicles isolated from plasma were identified as exosomes using a fluorescence probe specific for exosomes and three protein markers, Hsp70, CD9 and CD63, that are commonly used to identify exosome fraction. Fluorescence dye that stain dsDNA showed the association between exosomes and dsDNA. Plasma cfDNA concentration analysis showed more than 93% of amplifiable cfDNA in plasma is located in plasma exosomes. Storage of a blood sample showed significant increases in exosome count and exosome DNA concentration. This study provide evidence that a large proportion of plasma cfDNA is localized in exosomes. Exosome release from cells is a metabolic energy dependent process, thus suggesting active release of cfDNA from cells as a source of cfDNA in plasma.

Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells.

PubMed

García-Prat, Laura; Sousa-Victor, Pedro; Muñoz-Cánoves, Pura

2013-09-01

Aging of an organism is associated with the functional decline of tissues and organs, as well as a sharp decline in the regenerative capacity of stem cells. A prevailing view holds that the aging rate of an individual depends on the ratio of tissue attrition to tissue regeneration. Therefore, manipulations that favor the balance towards regeneration may prevent or delay aging. Skeletal muscle is a specialized tissue composed of postmitotic myofibers that contract to generate force. Satellite cells are the adult stem cells responsible for skeletal muscle regeneration. Recent studies on the biology of skeletal muscle and satellite cells in aging have uncovered the critical impact of systemic and niche factors on stem cell functionality and demonstrated the capacity of aged satellite cells to rejuvenate and increase their regenerative potential when exposed to a youthful environment. Here we review the current literature on the coordinated relationship between cell extrinsic and intrinsic factors that regulate the function of satellite cells, and ultimately determine tissue homeostasis and repair during aging, and which encourage the search for new anti-aging strategies. © 2013 The Authors Journal compilation © 2013 FEBS.

Regulation of hematopoietic stem cell aging by the small RhoGTPase Cdc42

PubMed Central

Geiger, Hartmut; Zheng, Yi

2015-01-01

Summary Aging of stem cells might be the underlying cause of tissue aging in tissue that in the adult heavily rely on stem cell activity, like the blood forming system. Hematopoiesis, the generation of blood forming cells, is sustained by hematopoietic stem cells. In this review article, we introduce the canonical set of phenotypes associated with aged HSCs, focus on the novel aging-associated phenotype apolarity caused by elevated activity of the small RhoGTPase in aged HSCs, disuccs the role of Cdc42 in hematopoiesis and describe that pharmacological inhibition of Cdc42 activity in aged HSCs results in functionally young and thus rejuvenated HSCs. PMID:25220425

Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.

PubMed

Zhang, Weiqi; Li, Jingyi; Suzuki, Keiichiro; Qu, Jing; Wang, Ping; Zhou, Junzhi; Liu, Xiaomeng; Ren, Ruotong; Xu, Xiuling; Ocampo, Alejandro; Yuan, Tingting; Yang, Jiping; Li, Ying; Shi, Liang; Guan, Dee; Pan, Huize; Duan, Shunlei; Ding, Zhichao; Li, Mo; Yi, Fei; Bai, Ruijun; Wang, Yayu; Chen, Chang; Yang, Fuquan; Li, Xiaoyu; Wang, Zimei; Aizawa, Emi; Goebl, April; Soligalla, Rupa Devi; Reddy, Pradeep; Esteban, Concepcion Rodriguez; Tang, Fuchou; Liu, Guang-Hui; Belmonte, Juan Carlos Izpisua

2015-06-05

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging. Copyright © 2015, American Association for the Advancement of Science.

Plasma Carotenoids, Tocopherols, and Retinol in the Age-Stratified (35-74 Years) General Population: A Cross-Sectional Study in Six European Countries.

PubMed

Stuetz, Wolfgang; Weber, Daniela; Dollé, Martijn E T; Jansen, Eugène; Grubeck-Loebenstein, Beatrix; Fiegl, Simone; Toussaint, Olivier; Bernhardt, Juergen; Gonos, Efstathios S; Franceschi, Claudio; Sikora, Ewa; Moreno-Villanueva, María; Breusing, Nicolle; Grune, Tilman; Bürkle, Alexander

2016-09-30

Blood micronutrient status may change with age. We analyzed plasma carotenoids, α-/γ-tocopherol, and retinol and their associations with age, demographic characteristics, and dietary habits (assessed by a short food frequency questionnaire) in a cross-sectional study of 2118 women and men (age-stratified from 35 to 74 years) of the general population from six European countries. Higher age was associated with lower lycopene and α-/β-carotene and higher β-cryptoxanthin, lutein, zeaxanthin, α-/γ-tocopherol, and retinol levels. Significant correlations with age were observed for lycopene ( r = -0.248), α-tocopherol ( r = 0.208), α-carotene ( r = -0.112), and β-cryptoxanthin ( r = 0.125; all p < 0.001). Age was inversely associated with lycopene (-6.5% per five-year age increase) and this association remained in the multiple regression model with the significant predictors (covariables) being country, season, cholesterol, gender, smoking status, body mass index (BMI (kg/m²)), and dietary habits. The positive association of α-tocopherol with age remained when all covariates including cholesterol and use of vitamin supplements were included (1.7% vs. 2.4% per five-year age increase). The association of higher β-cryptoxanthin with higher age was no longer statistically significant after adjustment for fruit consumption, whereas the inverse association of α-carotene with age remained in the fully adjusted multivariable model (-4.8% vs. -3.8% per five-year age increase). We conclude from our study that age is an independent predictor of plasma lycopene, α-tocopherol, and α-carotene.

Stem cell responses to plasma surface modified electrospun polyurethane scaffolds.

PubMed

Zandén, Carl; Hellström Erkenstam, Nina; Padel, Thomas; Wittgenstein, Julia; Liu, Johan; Kuhn, H Georg

2014-07-01

The topographical effects from functional materials on stem cell behavior are currently of interest in tissue engineering and regenerative medicine. Here we investigate the influence of argon, oxygen, and hydrogen plasma surface modification of electrospun polyurethane fibers on human embryonic stem cell (hESC) and rat postnatal neural stem cell (NSC) responses. The plasma gases were found to induce three combinations of fiber surface functionalities and roughness textures. On randomly oriented fibers, plasma treatments lead to substantially increased hESC attachment and proliferation as compared to native fibers. Argon plasma was found to induce the most optimal combination of surface functionality and roughness for cell expansion. Contact guided migration of cells and alignment of cell processes were observed on aligned fibers. Neuronal differentiation around 5% was found for all samples and was not significantly affected by the induced variations of surface functional group distribution or individual fiber topography. In this study the influence of argon, oxygen, and hydrogen plasma surface modification of electrospun polyurethane fibers on human embryonic stem cell and rat postnatal neural stem cell (NSC) responses is studied with the goal of clarifying the potential effects of functional materials on stem cell behavior, a topic of substantial interest in tissue engineering and regenerative medicine. Copyright © 2014 Elsevier Inc. All rights reserved.

Reduction in plasma total homocysteine through increasing folate intake in healthy individuals is not associated with changes in measures of antioxidant activity or oxidant damage.

PubMed

Moat, S J; Hill, M H; McDowell, I F W; Pullin, C H; Ashfield-Watt, P A L; Clark, Z E; Whiting, J M; Newcombe, R G; Lewis, M J; Powers, H J

2003-03-01

Various mechanisms have been proposed to explain the association between plasma total homocysteine (tHcy) and risk of cardiovascular disease, including oxidative activity of homocysteine. To explore the putative role of reactive oxygen species in the association between plasma tHcy and risk of cardiovascular disease in healthy individuals. A double-blind, placebo-controlled crossover intervention to increase folate intake through diet (increased consumption of folate-rich foods) and supplement (400 micro g folic acid) was carried out in 126 healthy men and women. Measurements were made of antioxidant activity in red blood cells and plasma, and products of oxidant damage in plasma. Diet and supplement-based interventions led to an increase in measures of folate status and a reduction in plasma tHcy. This was not associated with any significant change in measures of antioxidant activity (plasma and red blood cell glutathione peroxidase activity and red blood cell superoxide dismutase activity) or oxidant damage (plasma malondialdehyde), although an improvement in plasma total antioxidant capacity just failed to reach significance. In healthy individuals lowering plasma tHcy does not have any functional implications regarding oxidative damage.

Nanoparticles-cell association predicted by protein corona fingerprints

NASA Astrophysics Data System (ADS)

Palchetti, S.; Digiacomo, L.; Pozzi, D.; Peruzzi, G.; Micarelli, E.; Mahmoudi, M.; Caracciolo, G.

2016-06-01

In a physiological environment (e.g., blood and interstitial fluids) nanoparticles (NPs) will bind proteins shaping a ``protein corona'' layer. The long-lived protein layer tightly bound to the NP surface is referred to as the hard corona (HC) and encodes information that controls NP bioactivity (e.g. cellular association, cellular signaling pathways, biodistribution, and toxicity). Decrypting this complex code has become a priority to predict the NP biological outcomes. Here, we use a library of 16 lipid NPs of varying size (Ø ~ 100-250 nm) and surface chemistry (unmodified and PEGylated) to investigate the relationships between NP physicochemical properties (nanoparticle size, aggregation state and surface charge), protein corona fingerprints (PCFs), and NP-cell association. We found out that none of the NPs' physicochemical properties alone was exclusively able to account for association with human cervical cancer cell line (HeLa). For the entire library of NPs, a total of 436 distinct serum proteins were detected. We developed a predictive-validation modeling that provides a means of assessing the relative significance of the identified corona proteins. Interestingly, a minor fraction of the HC, which consists of only 8 PCFs were identified as main promoters of NP association with HeLa cells. Remarkably, identified PCFs have several receptors with high level of expression on the plasma membrane of HeLa cells.In a physiological environment (e.g., blood and interstitial fluids) nanoparticles (NPs) will bind proteins shaping a ``protein corona'' layer. The long-lived protein layer tightly bound to the NP surface is referred to as the hard corona (HC) and encodes information that controls NP bioactivity (e.g. cellular association, cellular signaling pathways, biodistribution, and toxicity). Decrypting this complex code has become a priority to predict the NP biological outcomes. Here, we use a library of 16 lipid NPs of varying size (Ø ~ 100-250 nm) and surface

Paternal age and intelligence: implications for age-related genomic changes in male germ cells.

PubMed

Malaspina, Dolores; Reichenberg, Avi; Weiser, Mark; Fennig, Shmuel; Davidson, Michael; Harlap, Susan; Wolitzky, Rachel; Rabinowitz, Jonathan; Susser, Ezra; Knobler, Haim Y

2005-06-01

A robust association between advancing paternal age and schizophrenia risk is reported, and genetic changes in the germ cells of older men are presumed to underlie the effect. If that is so, then the pathway may include effects on cognition, as those with premorbid schizophrenia are reported to have lower intelligence. There are also substantial genetic influences on intelligence, so de novo genetic events in male germ cells, which accompany advancing paternal age, may plausibly influence offspring intelligence. An association of paternal age with IQ in healthy adolescents may illuminate the mechanisms that link it to schizophrenia. We examined the association of paternal age and IQ scores using the Israeli Army Board data on 44 175 individuals from a richly described birth cohort, along with maternal age and other potential modifiers. A significant inverted U-shaped relationship was observed between paternal age and IQ scores, which was independent from a similar association of IQ scores with maternal age. These relationships were not significantly attenuated by controlling for multiple possible confounding factors, including the other parent's age, parental education, social class, sex and birth order, birth weight and birth complications. Overall, parental age accounted for approximately 2% of the total variance in IQ scores, with later paternal age lowering non-verbal IQ scores more than verbal IQ scores. We found independent effects of maternal and paternal age on offspring IQ scores. The paternal age effect may be explained by de novo mutations or abnormal methylation of paternally imprinted genes, whereas maternal age may affect fetal neurodevelopment through age-related alterations in the in-utero environment. The influence of late paternal age to modify non-verbal IQ may be related to the pathways that increase the risk for schizophrenia in the offspring of older fathers.

General intelligence is associated with subclinical inflammation in Nepalese children: A population-based plasma proteomics study.

PubMed

Lee, Sun Eun; West, Keith P; Cole, Robert N; Schulze, Kerry J; Wu, Lee Shu-Fune; Yager, James D; Groopman, John; Christian, Parul

2016-08-01

Improving child cognition in impoverished countries is a public health priority. Yet, biological pathways and associated biomarkers of impaired cognition remain poorly understood and largely unknown, respectively. This study aimed to explore and quantify associations between functional plasma protein biomarkers and childhood intellectual test performance. We applied proteomics to quantify proteins in plasma samples of 249 rural Nepalese children, 6-8years of age who, 1year later at 7-9years of age, were administered the Universal Nonverbal Intelligence Test (UNIT). Among 751 plasma proteins quantified, 22 were associated with UNIT scores, passing a false discovery rate threshold of 5.0% (q<0.05). UNIT scores were higher by 2.3-9.2 points for every 50% increase in relative abundance of two insulin-like growth factor binding proteins (IGFBPs), six subclasses of apolipoprotein (Apo) and transthyretin, and lower by 4.0-15.3 points for each 50% increase in relative abundance of 13 proteins predominantly involved in inflammation. Among them, IGFBP-acid labile subunit, orosomucoid 1 (ORM1), Apo C-I, and pyruvate kinase isoenzymes M1/M2 jointly explained 37% of the variance in UNIT scores. After additional adjustment for height-for-age Z-score and household socio-economic status as indicators of long-term nutritional and social stress, associations with 6 proteins involved in inflammation, including ORM1, α-1-antichymotrypsin, reticulocalbin 1, and 3 components of the complement cascade, remained significant (q<0.05). Using untargeted proteomics, stable, constitutive facets of subclinical inflammation were associated with lower developmental test performance in this rural South Asian child population. Plasma proteomics may offer opportunities to identify functional, antecedent biomarkers of child cognitive development. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells

PubMed Central

Grötsch, Bettina; Brachs, Sebastian; Lang, Christiane; Luther, Julia; Derer, Anja; Schlötzer-Schrehardt, Ursula; Bozec, Aline; Fillatreau, Simon; Berberich, Ingolf; Hobeika, Elias; Reth, Michael; Wagner, Erwin F.; Schett, Georg

2014-01-01

The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell–specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression. PMID:25288397

Effects of Almond- and Olive Oil-Based Docosahexaenoic- and Vitamin E-Enriched Beverage Dietary Supplementation on Inflammation Associated to Exercise and Age

PubMed Central

Capó, Xavier; Martorell, Miquel; Sureda, Antoni; Riera, Joan; Drobnic, Franchek; Tur, Josep Antoni; Pons, Antoni

2016-01-01

n-3-polyunsaturated fatty acids and polyphenols are potential key factors for the treatment and prevention of chronic inflammation associated to ageing and non-communicable diseases. The aim was to analyse effects of an almond and olive oil beverage enriched with α-tocopherol and docosahexaenoic, exercise and age on inflammatory plasma markers, and immune gene expression in peripheral blood mononuclear cells (PBMCs). Five young and five senior athletes who were supplemented for five weeks with a functional beverage performed a stress test under controlled conditions before and after beverage supplementation. Blood samples were taken immediately before and 1 h after each test. Plasma, erythrocytes and PBMCs were isolated. Beverage supplementation increased plasmatic Tumour Necrosis Factor α (TNFα) levels depending on age and exercise. Exercise increased plasma non esterified fatty acids (NEFAs), soluble Intercellular adhesion molecule 3 (sICAM3) and soluble L-selectin (sL-Selectin), and this increase was attenuated by the supplementation. Exercise increased PGE2 plasma levels in supplemented young and in senior placebo athletes. Exercise increased NFkβ-activated levels in PBMCs, which are primed to a pro-inflammatory response increasing pro-inflammatory genes expression after the exercise mainly in the young group after the supplementation. The functional beverage supplementation to young athletes enhances a pro-inflammatory circulating environment in response to the exercise that was less evident in the senior group. PMID:27735833

Effects of Almond- and Olive Oil-Based Docosahexaenoic- and Vitamin E-Enriched Beverage Dietary Supplementation on Inflammation Associated to Exercise and Age.

PubMed

Capó, Xavier; Martorell, Miquel; Sureda, Antoni; Riera, Joan; Drobnic, Franchek; Tur, Josep Antoni; Pons, Antoni

2016-10-09

n -3-polyunsaturated fatty acids and polyphenols are potential key factors for the treatment and prevention of chronic inflammation associated to ageing and non-communicable diseases. The aim was to analyse effects of an almond and olive oil beverage enriched with α-tocopherol and docosahexaenoic, exercise and age on inflammatory plasma markers, and immune gene expression in peripheral blood mononuclear cells (PBMCs). Five young and five senior athletes who were supplemented for five weeks with a functional beverage performed a stress test under controlled conditions before and after beverage supplementation. Blood samples were taken immediately before and 1 h after each test. Plasma, erythrocytes and PBMCs were isolated. Beverage supplementation increased plasmatic Tumour Necrosis Factor α (TNFα) levels depending on age and exercise. Exercise increased plasma non esterified fatty acids (NEFAs), soluble Intercellular adhesion molecule 3 (sICAM3) and soluble L-selectin (sL-Selectin), and this increase was attenuated by the supplementation. Exercise increased PGE2 plasma levels in supplemented young and in senior placebo athletes. Exercise increased NFkβ-activated levels in PBMCs, which are primed to a pro-inflammatory response increasing pro-inflammatory genes expression after the exercise mainly in the young group after the supplementation. The functional beverage supplementation to young athletes enhances a pro-inflammatory circulating environment in response to the exercise that was less evident in the senior group.

Plasma clots gelled by different amounts of calcium for stem cell delivery.

PubMed

Gessmann, Jan; Seybold, Dominik; Peter, Elvira; Schildhauer, Thomas Armin; Köller, Manfred

2013-01-01

Freshly prepared autologous plasma clots may serve as a carrier matrix for expanded multipotent mesenchymal stromal cells (MSCs) or bone marrow cells. By varying the calcium concentration, plasma clots with different properties can be produced. The purpose of this in vitro study was to determine the optimal calcium concentrations for the clotting process, intra-clot cell viability, and clot lysis. Different plasma clots were prepared by adding an equal volume of RPMI1640 (with or without MSCs) to citrate plasma (either containing platelets or platelet-free). Clotting was initiated by the addition of CaCl(2) (10 g/100 ml H(2)O, 10 % solution). The final concentration of CaCl(2) ranged from 1 to 10 % by volume of plasma. Viability and distribution of the MSCs were analysed by calcein-AM/propidium iodide staining. MSC-embedded plasma clots were dissolved with trypsin (0.25 %), and recovered cells were further incubated for 1 week under cell culture conditions. The viability of MSCs embedded in clots formed by the addition of 1-8 % by volume CaCl2 was not affected by incubation of up to 1 week. In contrast, clots produced by higher volumes of CaCl(2) solutions (9-10 % by volume of plasma) showed decreased numbers of viable cells. Intra-clot cell proliferation was highest in clots produced by addition of 5 % CaCl(2) by plasma volume. Osteocalcin release was not influenced in platelet-free plasma but decreased in platelet-containing plasma. Morphological analysis of stained recovered MSCs revealed that lysis of the plasma clot did not affect cell morphology or subsequent spontaneous proliferation. Clot formation and clot stability can be controlled by changing the concentration of CaCl(2) added to plasma. The addition of 5 % CaCl(2) produced a plasma clot with optimal results for stem cell delivery.

Age-associated increase in heterochromatic marks in murine and primate tissues.

PubMed

Kreiling, Jill A; Tamamori-Adachi, Mimi; Sexton, Alec N; Jeyapalan, Jessie C; Munoz-Najar, Ursula; Peterson, Abigail L; Manivannan, Jayameenakshi; Rogers, Elizabeth S; Pchelintsev, Nikolay A; Adams, Peter D; Sedivy, John M

2011-04-01

Chromatin is highly dynamic and subject to extensive remodeling under many physiologic conditions. Changes in chromatin that occur during the aging process are poorly documented and understood in higher organisms, such as mammals. We developed an immunofluorescence assay to quantitatively detect, at the single cell level, changes in the nuclear content of chromatin-associated proteins. We found increased levels of the heterochromatin-associated proteins histone macro H2A (mH2A) and heterochromatin protein 1 beta (HP1β) in human fibroblasts during replicative senescence in culture, and for the first time, an age-associated increase in these heterochromatin marks in several tissues of mice and primates. Mouse lung was characterized by monophasic mH2A expression histograms at both ages, and an increase in mean staining intensity at old age. In the mouse liver, we observed increased age-associated localization of mH2A to regions of pericentromeric heterochromatin. In the skeletal muscle, we found two populations of cells with either low or high mH2A levels. This pattern of expression was similar in mouse and baboon, and showed a clear increase in the proportion of nuclei with high mH2A levels in older animals. The frequencies of cells displaying evidence of increased heterochromatinization are too high to be readily accounted for by replicative or oncogene-induced cellular senescence, and are prominently found in terminally differentiated, postmitotic tissues that are not conventionally thought to be susceptible to senescence. Our findings distinguish specific chromatin states in individual cells of mammalian tissues, and provide a foundation to investigate further the progressive epigenetic changes that occur during aging. © 2010 The Authors. Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Effects of atmospheric pressure cold plasma on human hepatocarcinoma cell and its 5-fluorouracil resistant cell line

NASA Astrophysics Data System (ADS)

Yang, H.; Lu, R.; Xian, Y.; Gan, L.; Lu, X.; Yang, X.

2015-12-01

Atmospheric pressure cold plasma showed selective killing efficiency on cancer cells in vitro and in vivo, which makes plasma a potential option for cancer therapy. However, the plasma effects on chemotherapeutic drugs-resistant cells are rarely to be found. In this paper, the effects of plasma on human hepatocellular carcinoma Bel7402 cells and 5-fluorouracil (5-FU) resistant Bel7402/5FU cells were intensively investigated. The results showed that plasma induced superior toxicity to Bel7402 cells compared with Bel7402/5FU cells. Incubation with plasma-treated medium for 20 s induced more than 85% death rate in Bel7402 cells, while the same death ratio was achieved when Bel7402/5FU cells were treated for as long as 300 s. The hydrogen peroxide in the medium played a leading role in the cytotoxicity effects. Further studies implicated that when the treatment time was shorter than 60 s, the depolarization of mitochondrial membrane potential and apoptosis occurred through the intracellular reactive oxygen species accumulation in Bel7402 cells. Molecular analysis showed an increase in the transcription factor activity for AP-1, NF-кB, and p53 in Bel7402 cells. No obvious damage could be detected in plasma-treated Bel7402/5FU cells due to the strong intracellular reactive oxygen stress scavenger system.

Sinonasal inflammatory myofibroblastic pseudotumor (plasma cell granuloma).

PubMed

Arpacı, Rabia Bozdoğan; Kara, Tuba; Özyedek, Esen; Serinsöz, Ebru; Vayısoğlu, Yusuf; Özgür, Anıl; Arpacı, Taner; Özcan, Cengiz

2015-01-01

Inflammatory myofibroblastic pseudotumor (plasma cell granuloma) is a soft tissue lesion consisting of myofibroblasts, mature lymphocytes, histiocytes, plasma cells, eosinophils, and extracellular collagen. Various sites in the body may harbor these lesions. Lungs, omentum, intestines, mesentery, and urinary system are the most susceptible areas. It is usually seen in children and young adults. The lesion is rarely detected in the head and neck region. The orbit and the upper respiratory system are the most common localizations in the head and neck region. Sinonasal tract is a rare site of involvement. The differential diagnosis includes squamous cell carcinoma (spindle cell variant), inflammatory fibrosarcoma, leiomyosarcoma, schwannoma, and nonspecific inflammation. Our patient who had a sinonasal mass showed a benign tumor consisting of spindle tumor cells and inflammatory cells histopathologically. This case was presented due to its rare existence to this site.

Lipaemic plasma induces haemolysis in resuspended red cell concentrate.

PubMed

Bashir, S; Wiltshire, M; Cardigan, R; Thomas, S

2013-04-01

We investigated whether haemolysis in red cells suspended in plasma was affected by the lipid content and/or methylene blue (MB) treatment of fresh-frozen plasma (FFP). We also investigated whether haemolysis was affected by the conditions under which lipaemic plasma was stored. Study 1: Visibly lipaemic (n = 22) or nonlipaemic FFP (n = 24) units were thawed, pooled and split into identical pairs, one of which was MB treated. These units were used to resuspend red cell concentrates (RCC) and tested for haemolysis immediately and after 24 and 48 h of storage at 2-6°C. Study 2: Fresh plasma was aliquoted into 15-ml tubes and stored in one of four ways as follows: room temperature; 2-6°C; frozen and thawed; or twice frozen and thawed. A sample of RCC was resuspended in each of these plasmas and haemolysis measured after 2 h. Study 3: Plasma was divided into 15-ml tubes and stored as in study 2 followed by storage left standing upright in a refrigerator (2-6°C) for 24 h (with the exception of the room temperature sample). Plasma was separated into top, middle and bottom fractions and used to resuspend RCC that were assessed for haemolysis after 2 h. The levels of haemolysis in RCC were immediately greater when suspended in lipaemic plasma (0·70 ± 0·53% v 0·05 ± 0·06% for nonlipaemic plasma), which increased further on subsequent storage for 48 h (1·22 ± 0·40% v 0·15 ± 0·14% for nonlipaemic plasma). This was irrespective of whether plasma was MB treated. Lipaemic plasma stored frozen and then thawed resulted in the greatest haemolysis. In lipaemic plasma stored at 2-6°C, the chylomicron-rich top fraction caused the highest level of haemolysis. Haemolysis in red cells is increased in those suspended in lipaemic plasma and is dependent upon the storage conditions of that plasma prior to suspension. These data are relevant to the choice of plasma used to suspend red cells for neonatal exchange transfusion. © 2012 The Author(s). Vox Sanguinis © 2012

Investigation of cell-free DNA in canine plasma and its relation to disease.

PubMed

Burnett, Deborah L; Cave, Nicholas J; Gedye, Kristene R; Bridges, Janis P

2016-09-01

DNA is released from dying cells during apoptosis and necrosis. This cell-free DNA (cfDNA) diffuses into the plasma where it can be measured. In humans, an increase in cfDNA correlates with disease severity and prognosis. It was hypothesized that when DNA in canine plasma was measured by emission fluorometry without prior DNA extraction, the concentration of cfDNA would increase with disease severity. The diseased population consisted of 97 client-owned dogs. The clinically normal population consisted of nine client-owned dogs presenting for 'wellness screens', and 15 colony-owned Harrier Hounds. Plasma cfDNA was measured by fluorometry without prior DNA extraction. The effects of ex vivo storage conditions were evaluated in plasma from two clinically normal dogs. In all other dogs, plasma was separated within two hours of collection. The association between the cfDNA concentration in hospitalized dogs and a variety of clinical, clinicopathological and outcome variables was tested. The concentration of cfDNA was reliably measured when plasma was separated within two hours of blood collection. The diseased dogs had significantly higher cfDNA than clinically normal dogs (P < 0.001), and the more severe the disease, the higher the cfDNA when severity was categorized according to the American Society of Anesthesiologists (ASA) status (P < 0.001). Dogs that did not survive to discharge had significantly higher cfDNA concentrations than survivors (P = 0.02). Conclusions/Clinical Importance: The concentration of cfDNA in the plasma of diseased dogs is associated with disease severity and prognosis. Measurement of canine cfDNA could be a useful non-specific disease indicator and prognostic tool.

Cell cycle dependent changes in the plasma membrane organization of mammalian cells.

PubMed

Denz, Manuela; Chiantia, Salvatore; Herrmann, Andreas; Mueller, Peter; Korte, Thomas; Schwarzer, Roland

2017-03-01

Lipid membranes are major structural elements of all eukaryotic and prokaryotic organisms. Although many aspects of their biology have been studied extensively, their dynamics and lateral heterogeneity are still not fully understood. Recently, we observed a cell-to-cell variability in the plasma membrane organization of CHO-K1 cells (Schwarzer et al., 2014). We surmised that cell cycle dependent changes of the individual cells from our unsynchronized cell population account for this phenomenon. In the present study, this hypothesis was tested. To this aim, CHO-K1 cells were arrested in different cell cycle phases by chemical treatments, and the order of their plasma membranes was determined by various fluorescent lipid analogues using fluorescence lifetime imaging microscopy. Our experiments exhibit significant differences in the membrane order of cells arrested in the G2/M or S phase compared to control cells. Our single-cell analysis also enabled the specific selection of mitotic cells, which displayed a significant increase of the membrane order compared to the control. In addition, the lipid raft marker GPImYFP was used to study the lateral organization of cell cycle arrested cells as well as mitotic cells and freely cycling samples. Again, significant differences were found between control and arrested cells and even more pronounced between control and mitotic cells. Our data demonstrate a direct correlation between cell cycle progression and plasma membrane organization, underlining that cell-to-cell heterogeneities of membrane properties have to be taken into account in cellular studies especially at the single-cell level. Copyright © 2016 Elsevier B.V. All rights reserved.

Altered Antioxidant System Stimulates Dielectric Barrier Discharge Plasma-Induced Cell Death for Solid Tumor Cell Treatment

PubMed Central

Park, Daehoon; Choi, Eun H.

2014-01-01

This study reports the experimental findings and plasma delivery approach developed at the Plasma Bioscience Research Center, Korea for the assessment of antitumor activity of dielectric barrier discharge (DBD) for cancer treatment. Detailed investigation of biological effects occurring after atmospheric pressure non-thermal (APNT) plasma application during in vitro experiments revealed the role of reactive oxygen species (ROS) in modulation of the antioxidant defense system, cellular metabolic activity, and apoptosis induction in cancer cells. To understand basic cellular mechanisms, we investigated the effects of APNT DBD plasma on antioxidant defense against oxidative stress in various malignant cells as well as normal cells. T98G glioblastoma, SNU80 thyroid carcinoma, KB oral carcinoma and a non-malignant HEK293 embryonic human cell lines were treated with APNT DBD plasma and cellular effects due to reactive oxygen species were observed. Plasma significantly decreased the metabolic viability and clonogenicity of T98G, SNU80, KB and HEK293 cell lines. Enhanced ROS in the cells led to death via alteration of total antioxidant activity, and NADP+/NADPH and GSH/GSSG ratios 24 hours (h) post plasma treatment. This effect was confirmed by annexin V-FITC and propidium iodide staining. These consequences suggested that the failure of antioxidant defense machinery, with compromised redox status, might have led to sensitization of the malignant cells. These findings suggest a promising approach for solid tumor therapy by delivering a lethal dose of APNT plasma to tumor cells while sparing normal healthy tissues. PMID:25068311

Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory

PubMed Central

Kim, Ana; Fagan, Anne M; Goate, Alison M; Benzinger, Tammie LS; Morris, John C; Head, Denise

2015-01-01

Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in non-human animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts. PMID:25784293

Epigenetic Control of Stem Cell Potential During Homeostasis, Aging, and Disease

PubMed Central

Beerman, Isabel; Rossi, Derrick J.

2015-01-01

Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions. This review focuses on recent studies examining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-related disease. PMID:26046761

Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression.

PubMed

Graham, Susan M; Rajwans, Nimerta; Jaoko, Walter; Estambale, Benson B A; McClelland, R Scott; Overbaugh, Julie; Liles, W Conrad

2013-07-17

We aimed to determine whether endothelial activation biomarkers increase after HIV-1 acquisition, and whether biomarker levels measured in chronic infection would predict disease progression and death in HIV-1 seroconverters. HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition. Plasma levels of angiopoietin-1 and angiopoietin-2 (ANG-1, ANG-2) and soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were tested in stored samples from pre-infection, acute infection, and two chronic infection time points. We used nonparametric tests to compare biomarkers before and after HIV-1 acquisition, and Cox proportional-hazards regression to analyze associations with disease progression (CD4 < 200 cells/μl, stage IV disease, or antiretroviral therapy initiation) or death. Soluble ICAM-1 and VCAM-1 were elevated relative to baseline in all postinfection periods assessed (P < 0.0001). Soluble E-selectin and the ANG-2:ANG-1 ratio increased in acute infection (P = 0.0001), and ANG-1 decreased in chronic infection (P = 0.0004). Among 228 participants followed over 1028 person-years, 115 experienced disease progression or death. Plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death (adjusted hazard ratio 5.36, 95% confidence interval 1.99-14.44 per log10 increase), after adjustment for set point plasma viral load, age at infection, and soluble ICAM-1 levels. HIV-1 acquisition was associated with endothelial activation, with sustained elevations of soluble ICAM-1 and VCAM-1 postinfection. Soluble VCAM-1 may be an informative biomarker for predicting the risk of HIV-1 disease progression, morbidity, and mortality.

Aging, Atherosclerosis, and IGF-1

PubMed Central

Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung

2012-01-01

Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1–induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging. PMID:22491965

Plasma Protein Pentosidine and Carboxymethyllysine, Biomarkers for Age-related Macular Degeneration*

PubMed Central

Ni, Jiaqian; Yuan, Xianglin; Gu, Jiayin; Yue, Xiuzhen; Gu, Xiaorong; Nagaraj, Ram H.; Crabb, John W.

2009-01-01

Age-related macular degeneration (AMD) causes severe vision loss in the elderly; early identification of AMD risk could help slow or prevent disease progression. Toward the discovery of AMD biomarkers, we quantified plasma protein Nε-carboxymethyllysine (CML) and pentosidine from 58 AMD and 32 control donors. CML and pentosidine are advanced glycation end products that are abundant in Bruch membrane, the extracellular matrix separating the retinal pigment epithelium from the blood-bearing choriocapillaris. We measured CML and pentosidine by LC-MS/MS and LC-fluorometry, respectively, and found higher mean levels of CML (∼54%) and pentosidine (∼64%) in AMD (p < 0.0001) relative to normal controls. Plasma protein fructosyl-lysine, a marker of early glycation, was found by amino acid analysis to be in equal amounts in control and non-diabetic AMD donors, supporting an association between AMD and increased levels of CML and pentosidine independent of other diseases like diabetes. Carboxyethylpyrrole (CEP), an oxidative modification from docosahexaenoate-containing lipids and also abundant in AMD Bruch membrane, was elevated ∼86% in the AMD cohort, but autoantibody titers to CEP, CML, and pentosidine were not significantly increased. Compellingly higher mean levels of CML and pentosidine were present in AMD plasma protein over a broad age range. Receiver operating curves indicate that CML, CEP adducts, and pentosidine alone discriminated between AMD and control subjects with 78, 79, and 88% accuracy, respectively, whereas CML in combination with pentosidine provided ∼89% accuracy, and CEP plus pentosidine provided ∼92% accuracy. Pentosidine levels appeared slightly altered in AMD patients with hypertension and cardiovascular disease, indicating further studies are warranted. Overall this study supports the potential utility of plasma protein CML and pentosidine as biomarkers for assessing AMD risk and susceptibility, particularly in combination with CEP

Childhood Chronic Physical Aggression Associates with Adult Cytokine Levels in Plasma

PubMed Central

Provençal, Nadine; Suderman, Matthew J.; Vitaro, Frank; Szyf, Moshe; Tremblay, Richard E.

2013-01-01

Background An increasing number of animal and human studies are indicating that inflammation is associated with behavioral disorders including aggression. This study investigates the association between chronic physical aggression during childhood and plasma cytokine levels in early adulthood. Methodology/Principal Findings Two longitudinal studies were used to select males on a chronic physical aggression trajectory from childhood to adolescence (n = 7) and a control group from the same background (n = 25). Physical aggression was assessed yearly by teachers from childhood to adolescence and plasma levels of 10 inflammatory cytokines were assessed at age 26 and 28 years. Compared to the control group, males on a chronic physical aggression trajectory from childhood to adolescence had consistently lower plasma levels of five cytokines: lower pro-inflammatory interleukins IL-1α (T(28.7) = 3.48, P = 0.002) and IL-6 (T(26.9) = 3.76, P = 0.001), lower anti-inflammatory interleukin IL-4 (T(27.1) = 4.91, P = 0.00004) and IL-10 (T(29.8) = 2.84, P = 0.008) and lower chemokine IL-8 (T(26) = 3.69, P = 0.001). The plasma levels of four cytokines accurately predicted aggressive and control group membership for all subjects. Conclusions/Significance Physical aggression of boys during childhood is a strong predictor of reduced plasma levels of cytokines in early adulthood. The causal and physiological relations underlying this association should be further investigated since animal data suggest that some cytokines such as IL-6 and IL-1β play a causal role in aggression. PMID:23922720

Upregulation of Glycolytic Enzymes, Mitochondrial Dysfunction and Increased Cytotoxicity in Glial Cells Treated with Alzheimer’s Disease Plasma

PubMed Central

Jayasena, Tharusha; Poljak, Anne; Braidy, Nady; Smythe, George; Raftery, Mark; Hill, Mark; Brodaty, Henry; Trollor, Julian; Kochan, Nicole; Sachdev, Perminder

2015-01-01

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with increased oxidative stress and neuroinflammation. Markers of increased protein, lipid and nucleic acid oxidation and reduced activities of antioxidant enzymes have been reported in AD plasma. Amyloid plaques in the AD brain elicit a range of reactive inflammatory responses including complement activation and acute phase reactions, which may also be reflected in plasma. Previous studies have shown that human AD plasma may be cytotoxic to cultured cells. We investigated the effect of pooled plasma (n = 20 each) from healthy controls, individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) on cultured microglial cells. AD plasma and was found to significantly decrease cell viability and increase glycolytic flux in microglia compared to plasma from healthy controls. This effect was prevented by the heat inactivation of complement. Proteomic methods and isobaric tags (iTRAQ) found the expression level of complement and other acute phase proteins to be altered in MCI and AD plasma and an upregulation of key enzymes involved in the glycolysis pathway in cells exposed to AD plasma. Altered expression levels of acute phase reactants in AD plasma may alter the energy metabolism of glia. PMID:25785936

Plasma cell leukemia: update on biology and therapy.

PubMed

Mina, Roberto; D'Agostino, Mattia; Cerrato, Chiara; Gay, Francesca; Palumbo, Antonio

2017-07-01

Plasma cell leukemia (PCL) is a rare, but very aggressive, plasma cell dyscrasia, representing a distinct clinicopathological entity as compared to multiple myeloma (MM), with peculiar biological and clinical features. A hundred times rarer than MM, the disease course is characterized by short remissions and poor survival. PCL is defined by an increased percentage (>20%) and absolute number (>2 × 10 9 /l) of plasma cells in the peripheral blood. PCL is defined as 'primary' when peripheral plasmacytosis is detected at diagnosis, 'secondary' when leukemization occurs in a patient with preexisting MM. Novel agents have revolutionized the outcomes of MM patients and have been introduced also for the treatment of PCL. Here, we provide an update on biology and treatment options for PCL.

Plasma markers of B-cell activation and clonality in pediatric liver and hematopoietic stem cell transplant recipients

PubMed Central

Engels, Eric A.; Savoldo, Barbara; Pfeiffer, Ruth M.; Costello, Rene; Zingone, Adriana; Heslop, Helen E.; Landgren, Ola

2012-01-01

Introduction Transplant recipients are at risk of post-transplant lymphoproliferative disease (PTLD). Methods: Thirty-six pediatric transplant recipients were evaluated (18 hematopoietic stem cell and 18 liver recipients; 12 had PTLD). We studied 207 longitudinal plasma samples from these recipients for three markers of B-cell activation or clonality: immunoglobulin free light chains (FLCs), soluble CD30 (sCD30), and monoclonal immunoglobulins (M-proteins). Results Kappa FLCs, lambda FLCs, and sCD30 were elevated in 20.8%, 28.0%, and 94.2% of plasma specimens, respectively. FLC and sCD30 levels increased significantly 1.18–1.82 fold per log10 Epstein Barr virus (EBV) load in peripheral blood. Five PTLD cases manifested elevated FLCs with an abnormal kappa/lambda ratio, suggesting monoclonal FLC production. M-proteins were present in 91% of PTLD cases, vs. 50–67% of other recipients with high or low EBV loads (p=0.13). Concordance of FLCs, M-proteins, and PTLD tumor light chain restriction was imperfect. For example, one PTLD case with an IgG lambda M-protein had a tumor that was kappa restricted, and another case with an M-protein had a T-cell PTLD. In an additional case, an IgM kappa M-protein and excess kappa FLCs were both detected in plasma at PTLD diagnosis; while the tumor was not restricted at diagnosis, kappa restriction was present 5 years later when the PTLD relapsed. Discussion Plasma markers of B-cell dysfunction are frequent following transplantation and associated with poor EBV control. These abnormal markers may be produced by oligoclonal B-cell populations or PTLD tumor cells, and could potentially help identify recipients at high risk of PTLD. PMID:23222884

Development of a microfluidic device for cell concentration and blood cell-plasma separation.

PubMed

Maria, M Sneha; Kumar, B S; Chandra, T S; Sen, A K

2015-12-01

This work presents design, fabrication and test of a microfluidic device which employs Fahraeus-Lindqvist and Zweifach-Fung effects for cell concentration and blood cell-plasma separation. The device design comprises a straight main channel with a series of branched channels placed symmetrically on both sides of the main channel. The design implements constrictions before each junction (branching point) in order to direct cells that would have migrated closer to the wall (naturally or after liquid extraction at a junction) towards the centre of the main channel. Theoretical and numerical analysis are performed for design of the microchannel network to ensure that a minimum flow rate ratio (of 2.5:1, main channel-to-side channels) is maintained at each junction and predict flow rate at the plasma outlet. The dimensions and location of the constrictions were determined using numerical simulations. The effect of presence of constrictions before the junctions was demonstrated by comparing the performances of the device with and without constrictions. To demonstrate the performance of the device, initial experiments were performed with polystyrene microbeads (10 and 15 μm size) and droplets. Finally, the device was used for concentration of HL60 cells and separation of plasma and cells in diluted blood samples. The cell concentration and blood-plasma purification efficiency was quantified using Haemocytometer and Fluorescence-Activated Cell Sorter (FACS). A seven-fold cell concentration was obtained with HL60 cells and a purification efficiency of 70 % and plasma recovery of 80 % was observed for diluted (1:20) blood sample. FACS was used to identify cell lysis and the cell viability was checked using Trypan Blue test which showed that more than 99 % cells are alive indicating the suitability of the device for practical use. The proposed device has potential to be used as a sample preparation module in lab on chip based diagnostic platforms.

Detection and quantification of virus DNA in plasma of patients with Epstein-Barr virus-associated diseases.

PubMed

Yamamoto, M; Kimura, H; Hironaka, T; Hirai, K; Hasegawa, S; Kuzushima, K; Shibata, M; Morishima, T

1995-07-01

Epstein-Barr virus (EBV) causes various diseases, such as infectious mononucleosis (IM), fatal IM, EBV-associated hemophagocytic syndrome (EBVAHS), and chronic active EBV infection (CAEBV). In the present study, cell-free EBV DNA was detected in the plasma of patients with EBV-associated diseases by PCR assay. The patients included 20 patients with IM, 2 patients with fatal IM, 4 patients with EBVAHS, 4 patients with CAEBV, and 38 healthy children (20 EBV seropositive and 18 EBV seronegative). In patients with IM, plasma samples were positive for EBV DNA in all patients (100%) in the acute phase and in 44% of the patients in the convalescent phase, but plasma samples from the 38 healthy control children were negative (0%) for EBV DNA. Quantitative PCR assay revealed that plasma from patients with IM contained the highest amount of virus DNA within 7 days following the onset of disease (mean, 6 x 10(4) copies per ml). The EBV DNA concentration decreased thereafter as the patients recovered. Plasma from patients with fatal IM contained more than 100 times more copies of EBV DNA (3 x 10(7) copies per ml) than plasma from patients with IM. Plasma from patients with the acute phase of EBVAHS contained 10 times more copies of EBV DNA (5 x 10(5) copies per ml) than plasma from IM, and then patients with the number of copies decreased similarly in both groups of patients in the convalescent phase (2 x 10(4) copies per ml). The amount of virus DNA in patients with CAEBV (6 x 10(4) copies per ml) was similar to that noted in patients with IM; however, it became higher (1 x 10(6) copies per ml) when the patients' clinical status deteriorated. These data suggest that the presence of cell-free EBV DNA in plasma is a common phenomenon in patients with EBV-associated diseases. The concentration of EBV DNA in plasma seems to be higher in patients with the more severe clinical categories of EBV diseases.

Treatment of oral cancer cells with nonthermal atmospheric pressure plasma jet

NASA Astrophysics Data System (ADS)

Yurkovich, James; Han, Xu; Coffey, Benjamin; Klas, Matej; Ptasinska, Sylwia

2012-10-01

Non-thermal atmospheric pressure plasmas are specialized types of plasma that are proposed as a new agent to induce death in cancer cells. The experimental phase of this study will test the application of such plasma to SCC-25 oral cancer cells to determine if it is possible to induce apoptosis or necrosis. Different sources are used on the cells to find a configuration which kills cancer cells but has no effect on normal cells. The sources have been developed based on the dielectric barrier discharge between two external electrodes surrounding a dielectric tube; such a configuration has been shown to induce breaks in DNA strands. Each configuration is characterized using an optical emission spectrophotometer and iCCD camera to determine the optimal conditions for inducing cell death. The cells are incubated after irradiation with plasma, and cell death is determined using microscopy imaging to identify antibody interaction within the cells. These studies are important for better understanding of plasma species interactions with cancer cells and mechanisms of DNA damage and at latter stage they will be useful for the development of advanced cancer therapy.

Quantitative identification of senescent cells in aging and disease.

PubMed

Biran, Anat; Zada, Lior; Abou Karam, Paula; Vadai, Ezra; Roitman, Lior; Ovadya, Yossi; Porat, Ziv; Krizhanovsky, Valery

2017-08-01

Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. By utilizing technology that combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than nonsenescent cells. Thus, this method provides a basis for quantitative assessment of senescent cells and it offers proof of principle for combination of different markers of senescence. It paves the way for screening of senescent cells for identification of new senescence biomarkers, genes that bypass senescence or senolytic compounds that eliminate senescent cells, thus enabling a deeper understanding of the senescent state in vivo. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.