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Chandra A, Law SF, Pignolo RJ. Changing landscape of hematopoietic and mesenchymal cells and their interactions during aging and in age-related skeletal pathologies. Mech Ageing Dev 2025; 225:112059. [PMID: 40220914 PMCID: PMC12103995 DOI: 10.1016/j.mad.2025.112059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/26/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors-the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence-a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity , reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.
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Affiliation(s)
- Abhishek Chandra
- Department of Physiology and Biomedical Engineering, USA; Department of Medicine, Divisions of Hospital Internal Medicine and Section on Geriatric Medicine and Gerontology, USA; Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA.
| | - Susan F Law
- Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA
| | - Robert J Pignolo
- Department of Physiology and Biomedical Engineering, USA; Department of Medicine, Divisions of Hospital Internal Medicine and Section on Geriatric Medicine and Gerontology, USA; Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA
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Alshevskaya A, Zhukova J, Lopatnikova J, Vasilyev F, Khutornoy I, Golikova E, Kireev F, Sennikov S. Nonlinear Dynamics of TNFR1 and TNFR2 Expression on Immune Cells: Genetic and Age-Related Aspects of Inflamm-Aging Mechanisms. Biomedicines 2025; 13:852. [PMID: 40299450 PMCID: PMC12024874 DOI: 10.3390/biomedicines13040852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 03/21/2025] [Accepted: 03/23/2025] [Indexed: 04/30/2025] Open
Abstract
Introduction: Immunosenescence alters TNF receptor expression (TNFR1 and TNFR2), contributing to chronic inflammation (inflamm-aging) and age-related diseases. Polymorphisms in TNFRSF1A and TNFRSF1B may influence receptor expression; however, their role in age-dependent modulation remains unclear. This study examines TNFR1/TNFR2 expression dynamics on T cells, B cells, and monocytes across different ages and evaluates the impact of genetic polymorphisms. Methods: PBMCs from 150 donors (18-60 years) were isolated via density-gradient centrifugation and cultured under spontaneous and LPS-stimulated conditions. TNFR1 and TNFR2 expression on immune cell subsets was quantified using flow cytometry with BD QuantiBRITE PE beads. SNP genotyping in TNFRSF1A and TNFRSF1B was performed via PCR with restriction analysis. Nonlinear age-related trends were assessed using polynomial approximation and inflection point analysis (Tukey's method). Results: Among the 23 analyzed TNF system parameters, the proportion of TNFR2+CD3+ T cells increased with age, whereas TNFR1+ and TNFR2+ monocyte populations showed significant negative correlations (p < 0.05). Inflection points (~27, 34-36, and 44-45 years) indicated nonlinear dynamics in TNFRs expression during aging. TNFR2 expression on T cells gradually increased and stabilized at later ages, whereas TNFR1 and TNFR2 expression on monocytes followed distinct declining trajectories. Genetic polymorphisms influenced correlation strength, but did not alter direction, demonstrating a conserved pattern of age-related receptor expression shifts. Conclusions: TNFR expression exhibits nonlinear, age-dependent alterations across immune cells, shaped by immunosenescence and genetic variability. The identified critical age intervals represent key phases of immune remodeling, where assessing TNFR expression may provide insights into inflamm-aging mechanisms and potential targets for immune modulation.
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Affiliation(s)
- Alina Alshevskaya
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow 119048, Russia; (A.A.); (J.L.); (E.G.)
| | - Julia Zhukova
- Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (J.Z.); (F.V.); (F.K.)
| | - Julia Lopatnikova
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow 119048, Russia; (A.A.); (J.L.); (E.G.)
- Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (J.Z.); (F.V.); (F.K.)
| | - Filipp Vasilyev
- Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (J.Z.); (F.V.); (F.K.)
- Institute of Medicine, Ammosov North-Eastern Federal University in Yakutsk, Yakutsk 677013, Russia
| | - Ivan Khutornoy
- Lomonosov Moscow State University, Moscow 119991, Russia;
| | - Elena Golikova
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow 119048, Russia; (A.A.); (J.L.); (E.G.)
| | - Fedor Kireev
- Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (J.Z.); (F.V.); (F.K.)
| | - Sergey Sennikov
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow 119048, Russia; (A.A.); (J.L.); (E.G.)
- Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia; (J.Z.); (F.V.); (F.K.)
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Landers‐Ramos RQ, Kim K, Heilman J, Evans WS, Addison O, Ranadive SM, Prior SJ. Peripheral blood mononuclear cell number and paracrine function in responses to a 50-km trail race: An exploratory study. Physiol Rep 2025; 13:e70255. [PMID: 39972513 PMCID: PMC11839398 DOI: 10.14814/phy2.70255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/29/2025] [Accepted: 02/10/2025] [Indexed: 02/21/2025] Open
Abstract
Peripheral blood mononuclear cells (PBMCs) represent a heterogeneous mix of cells with paracrine functions that may be altered following prolonged exercise. We determined the effect of ultramarathon running on PBMC paracrine function and PBMC subtype number. Recreational athletes participated in a 50 km ultramarathon. Blood was sampled from N = 7 at baseline, 10 km, 50 km, and 24 h post-race. PBMCs were isolated and cultured, and conditioned media was used for a HUVEC-based proliferation assay. CD31+, CD3+, and CD31+/CD3+ PBMCs were quantified at each time point. Proliferation increased from baseline to 50 km (p = 0.004) and was reduced from 50 km to 24 h post (p = 0.008). There was an increase in CD31+ PBMCs after 50 km (p = 0.014), returning to baseline at 24 h post-race (p = 0.246). CD3+ PBMC and CD31+/CD3+ PBMC numbers were reduced after 50 km (p = 0.001 and p = 0.002, respectively), returning to baseline levels 24 h post-race (p = 0.190 and p = 0.315, respectively). PBMC paracrine activity following a 50 km enhances endothelial cell proliferation. Alterations in PBMC subtypes after 50 km suggest a protective role of PBMCs in response to prolonged stresses of ultramarathon running.
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Affiliation(s)
| | - Katherine Kim
- Department of KinesiologyUniversity of MarylandCollege ParkMarylandUSA
| | - James Heilman
- Department of KinesiologyUniversity of MarylandCollege ParkMarylandUSA
| | - William S. Evans
- Department of Exercise ScienceElon UniversityElonNorth CarolinaUSA
| | - Odessa Addison
- Department of Physical Therapy and Rehabilitation ScienceUniversity of MarylandBaltimoreMarylandUSA
- Department of Veterans Affairs Baltimore Veterans Affairs Medical CenterGeriatric Research, Education and Clinical CenterBaltimoreMarylandUSA
| | | | - Steven J. Prior
- Department of KinesiologyUniversity of MarylandCollege ParkMarylandUSA
- Department of Veterans Affairs Baltimore Veterans Affairs Medical CenterGeriatric Research, Education and Clinical CenterBaltimoreMarylandUSA
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Agrawal S, Chowdhury Z, Jethani R. Primary Ovarian Angiosarcoma: Diagnostic Challenges and Conundrums. Discoveries (Craiova) 2024; 12:e198. [PMID: 39845895 PMCID: PMC11746002 DOI: 10.15190/d.2024.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/29/2024] [Accepted: 12/29/2024] [Indexed: 01/24/2025] Open
Abstract
Angiosarcoma is an extremely uncommon mesenchymal neoplasm overall and moreso in female genital organs such as the ovary. Diagnosing primary ovarian angiosarcoma remains challenging on clinical grounds due to the absence of specific clinical symptoms as well as on histopathological analysis especially in poorly differentiated subtypes due to non-specific and overlapping morphologic features. Misdiagnosis in such scenarios can be devastating as this tumor is clinically very aggressive. We describe a case of primary ovarian angiosarcoma in a 33-year-old multiparous female with bilateral ovarian masses and metastasis at diagnosis. Histopathologic appraisal revealed a poorly differentiated malignant tumor with varied differential diagnoses. The saviour in such a scenario was the immunohistochemistry findings, underlining the incredible utility of this technique in the precise diagnosis and evasion of misdiagnosis. This case accentuates the paramount importance of precise diagnostic modalities in shaping clinical practice and enriching the scientific understanding of rare and aggressive neoplasms. Against this backdrop, the potential pitfalls and pearls while dealing with this entity have been elucidated, along with a review of the recent literature.
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Affiliation(s)
- Sujata Agrawal
- Department of Oncopathology Homi Bhabha Cancer Hospital (HBCH) and Mahamana Pandit Madan Mohan Malviya Cancer Centre (MPMMCC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Varanasi, India
| | - Zachariah Chowdhury
- Department of Oncopathology Homi Bhabha Cancer Hospital (HBCH) and Mahamana Pandit Madan Mohan Malviya Cancer Centre (MPMMCC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Varanasi, India
| | - Roma Jethani
- Department of Oncopathology Homi Bhabha Cancer Hospital (HBCH) and Mahamana Pandit Madan Mohan Malviya Cancer Centre (MPMMCC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Varanasi, India
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Singh M, Patel B, Seo M, Ahn P, Wais N, Shen H, Nakka S, Kishore P, Venketaraman V. TB and HIV induced immunosenescence: where do vaccines play a role? FRONTIERS IN AGING 2024; 5:1385963. [PMID: 38903242 PMCID: PMC11188299 DOI: 10.3389/fragi.2024.1385963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/13/2024] [Indexed: 06/22/2024]
Abstract
This paper tackles the complex interplay between Human Immunodeficiency virus (HIV-1) and Mycobacterium tuberculosis (M. tuberculosis) infections, particularly their contribution to immunosenescence, the age-related decline in immune function. Using the current literature, we discuss the immunological mechanisms behind TB and HIV-induced immunosenescence and critically evaluate the BCG (Bacillus Calmette-Guérin) vaccine's role. Both HIV-1 and M. tuberculosis demonstrably accelerate immunosenescence: M. tuberculosis through DNA modification and heightened inflammation, and HIV-1 through chronic immune activation and T cell production compromise. HIV-1 and M. tuberculosis co-infection further hastens immunosenescence by affecting T cell differentiation, underscoring the need for prevention and treatment. Furthermore, the use of the BCG tuberculosis vaccine is contraindicated in patients who are HIV positive and there is a lack of investigation regarding the use of this vaccine in patients who develop HIV co-infection with possible immunosenescence. As HIV does not currently have a vaccine, we focus our review more so on the BCG vaccine response as a result of immunosenescence. We found that there are overall limitations with the BCG vaccine, one of which is that it cannot necessarily prevent re-occurrence of infection due to effects of immunosenescence or protect the elderly due to this reason. Overall, there is conflicting evidence to show the vaccine's usage due to factors involving its production and administration. Further research into developing a vaccine for HIV and improving the BCG vaccine is warranted to expand scientific understanding for public health and beyond.
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Affiliation(s)
- Mona Singh
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Bhumika Patel
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Michael Seo
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Phillip Ahn
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Nejma Wais
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Haley Shen
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - SriHarsha Nakka
- Kempegowda Institute of Medical Sciences, Bengaluru, Karnataka, India
- Masters of Public Health, Chamberlain University, Addison, IL, United States
| | - Priya Kishore
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
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Yang L, Dong X, Abuduaini B, Jiamali N, Seyiti Z, Shan XF, Gao XM. Development and validation of a nomogram to predict mortality risk in patients with ischemic heart disease. Front Cardiovasc Med 2023; 10:1115463. [PMID: 36873413 PMCID: PMC9978180 DOI: 10.3389/fcvm.2023.1115463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Background Ischemic Heart Disease (IHD) is the leading cause of death from cardiovascular disease. Currently, most studies have focused on factors influencing IDH or mortality risk, while few predictive models have been used for mortality risk in IHD patients. In this study, we constructed an effective nomogram prediction model to predict the risk of death in IHD patients by machine learning. Methods We conducted a retrospective study of 1,663 patients with IHD. The data were divided into training and validation sets in a 3:1 ratio. The least absolute shrinkage and selection operator (LASSO) regression method was used to screen the variables to test the accuracy of the risk prediction model. Data from the training and validation sets were used to calculate receiver operating characteristic (ROC) curves, C-index, calibration plots, and dynamic component analysis (DCA), respectively. Results Using LASSO regression, we selected six representative features, age, uric acid, serum total bilirubin, albumin, alkaline phosphatase, and left ventricular ejection fraction, from 31 variables to predict the risk of death at 1, 3, and 5 years in patients with IHD, and constructed the nomogram model. In the reliability of the validated model, the C-index at 1, 3, and 5 years was 0.705 (0.658-0.751), 0.705 (0.671-0.739), and 0.694 (0.656-0.733) for the training set, respectively; the C-index at 1, 3, and 5 years based on the validation set was 0.720 (0.654-0.786), 0.708 (0.650-0.765), and 0.683 (0.613-0.754), respectively. Both the calibration plot and the DCA curve are well-behaved. Conclusion Age, uric acid, total serum bilirubin, serum albumin, alkaline phosphatase, and left ventricular ejection fraction were significantly associated with the risk of death in patients with IHD. We constructed a simple nomogram model to predict the risk of death at 1, 3, and 5 years for patients with IHD. Clinicians can use this simple model to assess the prognosis of patients at the time of admission to make better clinical decisions in tertiary prevention of the disease.
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Affiliation(s)
- Long Yang
- College of Pediatrics, Xinjiang Medical University, Ürümqi, China
| | - Xia Dong
- Intensive Care Unit, Cardiovascular Center, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | | | | | - Zulihuma Seyiti
- College of Pediatrics, Xinjiang Medical University, Ürümqi, China
| | - Xue-Feng Shan
- Pediatric Cardiothoracic Surgery, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Xiao-Ming Gao
- Department of Cardiology, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China.,Xinjiang Key Laboratory of Medical Animal Model Research, Ürümqi, China.,Clinical Medical Research Institute, Xinjiang Medical University, Ürümqi, China
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7
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Ellis PS, Martins RR, Thompson EJ, Farhat A, Renshaw SA, Henriques CM. A subset of gut leukocytes has telomerase-dependent "hyper-long" telomeres and require telomerase for function in zebrafish. Immun Ageing 2022; 19:31. [PMID: 35820929 PMCID: PMC9277892 DOI: 10.1186/s12979-022-00287-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND Telomerase, the enzyme capable of elongating telomeres, is usually restricted in human somatic cells, which contributes to progressive telomere shortening with cell-division and ageing. T and B-cells cells are somatic cells that can break this rule and can modulate telomerase expression in a homeostatic manner. Whereas it seems intuitive that an immune cell type that depends on regular proliferation outbursts for function may have evolved to modulate telomerase expression it is less obvious why others may also do so, as has been suggested for macrophages and neutrophils in some chronic inflammation disease settings. The gut has been highlighted as a key modulator of systemic ageing and is a key tissue where inflammation must be carefully controlled to prevent dysfunction. How telomerase may play a role in innate immune subtypes in the context of natural ageing in the gut, however, remains to be determined. RESULTS Using the zebrafish model, we show that subsets of gut immune cells have telomerase-dependent"hyper-long" telomeres, which we identified as being predominantly macrophages and dendritics (mpeg1.1+ and cd45+mhcII+). Notably, mpeg1.1+ macrophages have much longer telomeres in the gut than in their haematopoietic tissue of origin, suggesting that there is modulation of telomerase in these cells, in the gut. Moreover, we show that a subset of gut mpeg1.1+ cells express telomerase (tert) in young WT zebrafish, but that the relative proportion of these cells decreases with ageing. Importantly, this is accompanied by telomere shortening and DNA damage responses with ageing and a telomerase-dependent decrease in expression of autophagy and immune activation markers. Finally, these telomerase-dependent molecular alterations are accompanied by impaired phagocytosis of E. coli and increased gut permeability in vivo. CONCLUSIONS Our data show that limiting levels of telomerase lead to alterations in gut immunity, impacting on the ability to clear pathogens in vivo. These are accompanied by increased gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing.
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Affiliation(s)
- Pam S Ellis
- The Bateson Centre, MRC-Arthritis Research UK Centre for Integrated Research Into Musculoskeletal Ageing and Department of Oncology and Metabolism, Healthy Lifespan Institute, University of Sheffield Medical School, Sheffield, UK
| | - Raquel R Martins
- The Bateson Centre, MRC-Arthritis Research UK Centre for Integrated Research Into Musculoskeletal Ageing and Department of Oncology and Metabolism, Healthy Lifespan Institute, University of Sheffield Medical School, Sheffield, UK
| | - Emily J Thompson
- The Bateson Centre, MRC-Arthritis Research UK Centre for Integrated Research Into Musculoskeletal Ageing and Department of Oncology and Metabolism, Healthy Lifespan Institute, University of Sheffield Medical School, Sheffield, UK
| | - Asma Farhat
- The Bateson Centre, MRC-Arthritis Research UK Centre for Integrated Research Into Musculoskeletal Ageing and Department of Oncology and Metabolism, Healthy Lifespan Institute, University of Sheffield Medical School, Sheffield, UK
| | - Stephen A Renshaw
- The Bateson Centre and Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
| | - Catarina M Henriques
- The Bateson Centre, MRC-Arthritis Research UK Centre for Integrated Research Into Musculoskeletal Ageing and Department of Oncology and Metabolism, Healthy Lifespan Institute, University of Sheffield Medical School, Sheffield, UK.
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Efared B, Sylla B, Hammas N, El Fatemi H, Chbani L. Unusual mucosal lesion: A case of rectal pseudolipomatosis in a 60-year-old patient. SAGE Open Med Case Rep 2019; 7:2050313X19849281. [PMID: 31105960 PMCID: PMC6503594 DOI: 10.1177/2050313x19849281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/16/2019] [Indexed: 11/15/2022] Open
Abstract
Pseudolipomatosis is a very rare benign pathologic condition of colorectal
mucosa. It is caused by the presence of gas bubbles in the intestinal mucosa.
The endoscopic and histologic aspects are misleading as they suggest adipocytic
or vascular lesions. We present herein a case of rectal pseudolipomatosis in a
60-year-old woman presenting with rectal bleeding. The endoscopic pattern was
not suggestive of the lesion, and the histopathologic analysis of the patient’s
rectal biopsies revealed characteristic features of pseudolipomatosis.
Rectocolic pseudolipomatosis is a very rare benign condition with challenging
clinicopathologic presentation. Clinicians and pathologists should be aware of
this uncommon lesion for correct diagnosis and appropriate clinical
management.
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Affiliation(s)
- Boubacar Efared
- Department of Pathology, Hassan II University Hospital, Fès, Morocco.,Department of Pathology, Faculté des Sciences de la Santé (FSS), Abdou-Moumouni University, Niamey, Niger
| | - Balandougou Sylla
- Department of Gastroenterology, Hassan II University Hospital, Fès, Morocco
| | - Nawal Hammas
- Department of Pathology, Hassan II University Hospital, Fès, Morocco.,Laboratory of Biomedical and Translational Research, Faculty of Medicine and Pharmacology, Sidi Mohamed Ben Abdellah University, Fès, Morocco
| | - Hinde El Fatemi
- Department of Pathology, Hassan II University Hospital, Fès, Morocco.,Laboratory of Biomedical and Translational Research, Faculty of Medicine and Pharmacology, Sidi Mohamed Ben Abdellah University, Fès, Morocco
| | - Laila Chbani
- Department of Pathology, Hassan II University Hospital, Fès, Morocco.,Laboratory of Biomedical and Translational Research, Faculty of Medicine and Pharmacology, Sidi Mohamed Ben Abdellah University, Fès, Morocco
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Landers-Ramos RQ, Sapp RM, Shill DD, Hagberg JM, Prior SJ. Exercise and Cardiovascular Progenitor Cells. Compr Physiol 2019; 9:767-797. [PMID: 30892694 DOI: 10.1002/cphy.c180030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Autologous stem/progenitor cell-based methods to restore blood flow and function to ischemic tissues are clinically appealing for the substantial proportion of the population with cardiovascular diseases. Early preclinical and case studies established the therapeutic potential of autologous cell therapies for neovascularization in ischemic tissues. However, trials over the past ∼15 years reveal the benefits of such therapies to be much smaller than originally estimated and a definitive clinical benefit is yet to be established. Recently, there has been an emphasis on improving the number and function of cells [herein generally referred to as circulating angiogenic cells (CACs)] used for autologous cell therapies. CACs include of several subsets of circulating cells, including endothelial progenitor cells, with proangiogenic potential that is largely exerted through paracrine functions. As exercise is known to improve CV outcomes such as angiogenesis and endothelial function, much attention is being given to exercise to improve the number and function of CACs. Accordingly, there is a growing body of evidence that acute, short-term, and chronic exercise have beneficial effects on the number and function of different subsets of CACs. In particular, recent studies show that aerobic exercise training can increase the number of CACs in circulation and enhance the function of isolated CACs as assessed in ex vivo assays. This review summarizes the roles of different subsets of CACs and the effects of acute and chronic exercise on CAC number and function, with a focus on the number and paracrine function of circulating CD34+ cells, CD31+ cells, and CD62E+ cells. © 2019 American Physiological Society. Compr Physiol 9:767-797, 2019.
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Affiliation(s)
- Rian Q Landers-Ramos
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA.,Education and Clinical Center, Baltimore Veterans Affairs Geriatric Research, Baltimore, Maryland, USA.,University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
| | - Ryan M Sapp
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA
| | - Daniel D Shill
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA
| | - James M Hagberg
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA
| | - Steven J Prior
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA.,Education and Clinical Center, Baltimore Veterans Affairs Geriatric Research, Baltimore, Maryland, USA.,University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
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10
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O'Carroll L, Wardrop B, Murphy RP, Ross MD, Harrison M. Circulating angiogenic cell response to sprint interval and continuous exercise. Eur J Appl Physiol 2019; 119:743-752. [PMID: 30673849 DOI: 10.1007/s00421-018-04065-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 12/24/2018] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Although commonly understood as immune cells, certain T lymphocyte and monocyte subsets have angiogenic potential, contributing to blood vessel growth and repair. These cells are highly exercise responsive and may contribute to the cardiovascular benefits seen with exercise. PURPOSE To compare the effects of a single bout of continuous (CONTEX) and sprint interval exercise (SPRINT) on circulating angiogenic cells (CAC) in healthy recreationally active adults. METHODS Twelve participants (aged 29 ± 2 years, BMI 25.5 ± 0.9 kg m- 2, [Formula: see text]peak 44.3 ± 1.8 ml kg- 1 min- 1; mean ± SEM) participated in the study. Participants completed a 45-min bout of CONTEX at 70% peak oxygen uptake and 6 × 20 s sprints on a cycle ergometer, in a counterbalanced design. Blood was sampled pre-, post-, 2 h and 24 h post-exercise for quantification of CAC subsets by whole blood flow cytometric analysis. Angiogenic T lymphocytes (TANG) and angiogenic Tie2-expressing monocytes (TEM) were identified by the expression of CD31 and Tie2, respectively. RESULTS Circulating (cells µL- 1) CD3+CD31+ TANG increased immediately post-exercise in both trials (p < 0.05), with a significantly greater increase (p < 0.05) following SPRINT (+ 57%) compared to CONTEX (+ 14%). Exercise increased (p < 0.05) the expression of the chemokine receptor CXCR4 on TANG at 24 h. Tie2-expressing classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) monocytes and circulating CD34+CD45dim progenitor cells were higher post-exercise in SPRINT, but unchanged in CONTEX. All post-exercise increases in SPRINT were back to pre-exercise levels at 2 h and 24 h. CONCLUSION Acute exercise transiently increases circulating TANG, TEM and progenitor cells with greater increases evident following very high intensity sprint exercise than following prolonged continuous paced endurance exercise.
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Affiliation(s)
- Louis O'Carroll
- Department of Sport and Exercise Science, Waterford Institute of Technology, Waterford, Ireland
| | - Bruce Wardrop
- Department of Sport and Exercise Science, Waterford Institute of Technology, Waterford, Ireland
| | - Ronan P Murphy
- School of Health and Human Performance, Dublin City University, Dublin, Ireland
| | - Mark D Ross
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, UK
| | - Michael Harrison
- Department of Sport and Exercise Science, Waterford Institute of Technology, Waterford, Ireland.
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Ross M, Ingram L, Taylor G, Malone E, Simpson RJ, West D, Florida‐James G. Older men display elevated levels of senescence-associated exercise-responsive CD28 null angiogenic T cells compared with younger men. Physiol Rep 2018; 6:e13697. [PMID: 29939490 PMCID: PMC6016626 DOI: 10.14814/phy2.13697] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/03/2018] [Accepted: 04/06/2018] [Indexed: 12/19/2022] Open
Abstract
Aging is associated with elevated cardiovascular disease risk. As a result of aging, endothelial dysfunction develops, partly due to a reduction in vascular regenerative ability. CD31+ T cells (angiogenic T cells; TANG ) possess highly angiogenic capabilities; however, these cells are significantly reduced in older populations. In addition, older populations possess significantly higher senescent and highly differentiated T-cell levels in circulation, and these are reported to be highly exercise responsive. We investigated whether older adults display greater levels of circulating senescent (CD28null ) TANG cells and whether these cells were more exercise responsive than CD28+ TANG cells. Young (18-25 years; n = 9) and older (60-75 years; n = 10) healthy men undertook a 30-min cycling bout at 70% V˙O2 peak, with circulating TANG cells (CD3+ CD31+ CD28+/null ; including CD4+ and CD8+ subsets) measured preexercise, postexercise, and 1 h post exercise by flow cytometry. Older adults displayed reduced basal levels of TANG cells (mean ± SEM: 410 ± 81 vs. 784 ± 118 cells·μL, P = 0.017), despite a greater proportion of these cells being CD28null (26.26 ± 5.08 vs. 13.36 ± 2.62%, P = 0.044). Exercise significantly increased the circulating number of TANG cells in both young and older men. However, in older men alone, exercise preferentially mobilized CD28null CD8+ TANG cells compared with CD28+ TANG cells (time × phenotype interaction: P = 0.022; Δ74 ± 29 vs. Δ27 ± 15 cells·μL, P = 0.059), with no such difference observed between these phenotypes in the young population. In conclusion, this is the first study to demonstrate that despite observing lower circulating numbers of TANG cells, older adults display greater levels of senescent TANG cells in comparison with younger individuals, and these cells are more exercise responsive than CD28+ TANG cells. Lower number of circulating TANG and greater levels of senescent-associated CD28null TANG may contribute to greater CVD risk with advancing age.
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Affiliation(s)
- Mark Ross
- School of Applied SciencesEdinburgh Napier UniversityEdinburghUnited Kingdom
| | - Lesley Ingram
- School of Applied SciencesEdinburgh Napier UniversityEdinburghUnited Kingdom
| | - Guy Taylor
- Institute of Cellular MedicineNewcastle UniversityNewcastleUnited Kingdom
| | - Eva Malone
- School of Applied SciencesEdinburgh Napier UniversityEdinburghUnited Kingdom
| | - Richard J. Simpson
- Department of Nutritional SciencesDepartment of PediatricsDepartment of ImmunobiologyThe University of ArizonaTucsonArizona
| | - Dan West
- Institute of Cellular MedicineNewcastle UniversityNewcastleUnited Kingdom
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12
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Rippberger PL, Emeny RT, Mackenzie TA, Bartels SJ, Batsis JA. The association of sarcopenia, telomere length, and mortality: data from the NHANES 1999-2002. Eur J Clin Nutr 2018; 72:255-263. [PMID: 29238037 PMCID: PMC5809180 DOI: 10.1038/s41430-017-0011-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Revised: 07/19/2017] [Accepted: 09/01/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND/OBJECTIVES Sarcopenia is defined as the loss of muscle mass or function with aging and is associated with adverse outcomes. Telomere shortening is associated with mortality, yet its relationship with sarcopenia is unknown. SUBJECTS/METHODS Adults ≥60 years from the 1999-2002 NHANES with body composition measures were identified. Sarcopenia was defined using the two Foundation for the National Institute of Health definitions: appendicular lean mass (ALM) (men <19.75; women <15.02 kg); or ALM divided by body mass index (BMI) (ALM:BMI, men <0.789; women <0.512). Telomere length was assessed using quantitative PCR. Regression models predicted telomere length with sarcopenia (referent = no sarcopenia). RESULTS We identified 2672 subjects. Mean age was 70.9 years (55.5% female). Prevalence of ALM and ALM:BMI sarcopenia was 29.2 and 22.1%. Deaths were higher in persons with sarcopenia as compared to those without sarcopenia (ALM: 46.4 vs. 33.4%, p < 0.001; ALM:BMI: 46.7 vs. 33.2%, p < 0.001). No adjusted differences were observed in telomere length in those with/without sarcopenia (ALM: 0.90 vs. 0.92, p = 0.74, ALM:BMI 0.89 vs. 0.92, p = 0.24). In men with ALM:BMI-defined sarcopenia, adjusted telomere length was significantly lower compared to men without sarcopenia (0.85 vs. 0.91, p = 0.013). With sarcopenia, we did not observe a significant association between telomere length and mortality (ALM: HR 1.11 [0.64,1.82], p = 0.68; ALM:BMI: HR 0.97 [0.53,1.77], p = 0.91), but noted significance in those without sarcopenia with mortality (ALM: HR 0.59 [0.40,0.86], p = 0.007; ALM:BMI: HR 0.62 [0.42,0.91]; p = 0.01). CONCLUSIONS We observed a potentially inverse relationship between telomere length and mortality in those without sarcopenia but did not observe a significant relationship between telomere length and mortality in the presence of sarcopenia.
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Affiliation(s)
- Peter L Rippberger
- University of New England College of Osteopathic Medicine, Biddeford, ME, USA
| | - Rebecca T Emeny
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- The Dartmouth Institute for Health Policy & Clinical Practice, Lebanon, NH, USA
| | - Todd A Mackenzie
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- The Dartmouth Institute for Health Policy & Clinical Practice, Lebanon, NH, USA
| | - Stephen J Bartels
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- The Dartmouth Institute for Health Policy & Clinical Practice, Lebanon, NH, USA
- Dartmouth Centers for Health and Aging, Dartmouth College, Hanover, NH, USA
- Health Promotion Research Center at Dartmouth, Lebanon, NH, USA
| | - John A Batsis
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
- The Dartmouth Institute for Health Policy & Clinical Practice, Lebanon, NH, USA.
- Dartmouth Centers for Health and Aging, Dartmouth College, Hanover, NH, USA.
- Health Promotion Research Center at Dartmouth, Lebanon, NH, USA.
- Section of General Internal Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
- Dartmouth Weight & Wellness Center, Lebanon, NH, USA.
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13
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Ross MD, Malone EM, Simpson R, Cranston I, Ingram L, Wright GP, Chambers G, Florida-James G. Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men. Am J Physiol Heart Circ Physiol 2017; 314:H392-H402. [PMID: 29167123 DOI: 10.1152/ajpheart.00592.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Aging is associated with a dysfunctional endothelial phenotype as well as reduced angiogenic capabilities. Exercise exerts beneficial effects on the cardiovascular system, possibly by increasing/maintaining the number and/or function of circulating angiogenic cells (CACs), which are known to decline with age. However, the relationship between cardiorespiratory fitness (CRF) and age-related changes in the frequency of CACs, as well as the exercise-induced responsiveness of CACs in older individuals, has not yet been determined. One-hundred seven healthy male volunteers, aged 18-75 yr, participated in study 1. CRF was estimated using a submaximal cycling ergometer test. Circulating endothelial progenitor cells (EPCs), angiogenic T cells (TANG), and their chemokine (C-X-C motif) receptor 4 (CXCR4) cell surface receptor expression were enumerated by flow cytometry using peripheral blood samples obtained under resting conditions before the exercise test. In study 2, 17 healthy men (8 young men, 18-25 yr; 9 older men, 60-75 yr) were recruited, and these participants undertook a 30-min cycling exercise bout at 70% maximal O2 consumption, with CACs enumerated before and immediately after exercise. Age was inversely associated with both CD34+ progenitor cells ( r2 = -0.140, P = 0.000) and TANG ( r2 = -0.176, P = 0.000) cells as well as CXCR4-expressing CACs (CD34+: r2 = -0.167, P = 0.000; EPCs: r2 = -0.098, P = 0.001; TANG: r2 = -0.053, P = 0.015). However, after correcting for age, CRF had no relationship with either CAC subset. In addition, older individuals displayed attenuated exercise-induced increases in CD34+ progenitor cells, TANG, CD4+, TANG, and CD8+CXCR4+ TANG cells. Older men display lower CAC levels, which may contribute to increased risk of cardiovascular disease, and older adults display an impaired exercise-induced responsiveness of these cells. NEW & NOTEWORTHY Older adults display lower circulating progenitor cell and angiogenic T cell counts compared with younger individuals independently of cardiometabolic risk factors and cardiorespiratory fitness. Older adults also display impaired exercise-induced mobilization of these vasculogenic cells.
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Affiliation(s)
- Mark D Ross
- School of Applied Sciences, Edinburgh Napier University , Edinburgh , United Kingdom
| | - Eva M Malone
- School of Applied Sciences, Edinburgh Napier University , Edinburgh , United Kingdom
| | - Richard Simpson
- Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona , Tucson, Arizona.,Department of Pediatrics, College of Medicine, University of Arizona , Tucson, Arizona
| | - Islay Cranston
- School of Applied Sciences, Edinburgh Napier University , Edinburgh , United Kingdom
| | - Lesley Ingram
- School of Applied Sciences, Edinburgh Napier University , Edinburgh , United Kingdom
| | - Graham P Wright
- School of Applied Sciences, Edinburgh Napier University , Edinburgh , United Kingdom
| | - George Chambers
- School of Applied Sciences, Edinburgh Napier University , Edinburgh , United Kingdom
| | - Geraint Florida-James
- School of Applied Sciences, Edinburgh Napier University , Edinburgh , United Kingdom
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14
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Contreras A, Orozco AF, Resende M, Schutt RC, Traverse JH, Henry TD, Lai D, Cooke JP, Bolli R, Cohen ML, Moyé L, Pepine CJ, Yang PC, Perin EC, Willerson JT, Taylor DA. Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials. Basic Res Cardiol 2017; 112:3. [PMID: 27882430 PMCID: PMC5760218 DOI: 10.1007/s00395-016-0592-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 11/14/2016] [Indexed: 12/13/2022]
Abstract
Autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST-segment elevation myocardial infarction (STEMI) has produced inconsistent results, possibly due to BM-MNC product heterogeneity. Patient-specific cardiovascular risk factors (CRFs) may contribute to variations in BM-MNC composition. We sought to identify associations between BM-MNC subset frequencies and specific CRFs in STEMI patients. Bone marrow was collected from 191 STEMI patients enrolled in the CCTRN TIME and LateTIME trials. Relationships between BM-MNC subsets and CRFs were determined with multivariate analyses. An assessment of CRFs showed that hyperlipidemia and hypertension were associated with a higher frequency of CD11b+ cells (P = 0.045 and P = 0.016, respectively). In addition, we found that females had lower frequencies of CD11b+ (P = 0.018) and CD45+CD14+ (P = 0.028) cells than males, age was inversely associated with the frequency of CD45+CD31+ cells (P = 0.001), smoking was associated with a decreased frequency of CD45+CD31+ cells (P = 0.013), glucose level was positively associated with the frequency of CD45+CD3+ cells, and creatinine level (an indicator of renal function) was inversely associated with the frequency of CD45+CD3+ cells (P = 0.015). In conclusion, the frequencies of monocytic, lymphocytic, and angiogenic BM-MNCs varied in relation to patients' CRFs. These phenotypic variations may affect cell therapy outcomes and might be an important consideration when selecting patients for and reviewing results from autologous cell therapy trials.
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Affiliation(s)
| | | | | | - Robert C Schutt
- Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Research Institute, Houston, TX, USA
| | - Jay H Traverse
- Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, MN, USA
| | | | - Dejian Lai
- UT Health School of Public Health, Houston, TX, USA
| | - John P Cooke
- Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Research Institute, Houston, TX, USA
| | | | | | - Lem Moyé
- UT Health School of Public Health, Houston, TX, USA.
| | - Carl J Pepine
- College of Medicine, University of Florida, Gainesville, FL, USA
| | - Phillip C Yang
- Stanford University School of Medicine, Stanford, CA, USA
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15
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Landers-Ramos RQ, Sapp RM, VandeWater E, Macko J, Robinson S, Wang Y, Chin ER, Spangenburg EE, Prior SJ, Hagberg JM. Investigating the extremes of the continuum of paracrine functions in CD34-/CD31+ CACs across diverse populations. Am J Physiol Heart Circ Physiol 2016; 312:H162-H172. [PMID: 27793853 DOI: 10.1152/ajpheart.00342.2016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 09/30/2016] [Accepted: 10/14/2016] [Indexed: 11/22/2022]
Abstract
Paracrine function of circulating angiogenic cells (CACs) is thought to contribute to vascular maintenance. We previously identified S100A8 and S100A9 secreted from physically inactive individuals' CD34-/CD31+ CACs as negative regulators of capillary-like network formation. The purpose of this study was to investigate further the extremes of the continuum of CAC paracrine actions using two distinctly different groups representing "healthy" and "impaired" CAC function. We aimed to determine how capillary-like network formation in human umbilical vein endothelial cells (HUVECs) is affected by S100A8 and S100A9 in concentrations secreted by CACs from different ends of the health spectrum. CD34-/CD31+ CACs were isolated and cultured from 10 impaired function individuals defined as older (50-89 yr), non-ST-elevation myocardial infarction patients and 10 healthy individuals defined as younger (18-35 yr), healthy individuals, and conditioned media (CM) was generated. CM from the impaired function group's CACs significantly diminished network formation compared with CM from the healthy group (P < 0.05). We identified elevations in S100A8, S100A9, and S100A8/A9 in the CM from the impaired function group (P < 0.05). Pretreatment of HUVECs with inhibitors to a known S100A8 and S100A9 receptor, Toll-like receptor 4 (TLR4), but not receptor for advanced glycation end products, improved HUVEC network formation (P < 0.05) compared with CM alone in the impaired function conditions. Exposure of HUVECs to the TLR4 signaling inhibitor also blocked recombinant S100A8- and S100A9-mediated reductions in network formation. Collectively, the results suggest that the mechanisms behind impaired CAC CD34-/CD31+ CM-mediated reductions in capillary-like network formation involve secretion of S100A8 and S100A9 and binding of these proteins to TLR4 receptors on HUVECs. NEW & NOTEWORTHY S100A8 and S100A9 proteins in concentrations secreted by CD34-/CD31+ circulating angiogenic cells (CACs) with impaired function reduce endothelial cell capillary-like network formation. These effects appear to be mediated by Toll-like receptor 4 and are absent with S100A8 and S100A9 in concentrations secreted by healthy CD34-/CD31+ CACs.
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Affiliation(s)
- Rian Q Landers-Ramos
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
| | - Ryan M Sapp
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
| | - Emily VandeWater
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
| | - Jennifer Macko
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
| | - Shawn Robinson
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Yan Wang
- Proteomics Core Facility, College of Computer, Mathematics, and Natural Sciences, University of Maryland, College Park, Maryland; and
| | - Eva R Chin
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
| | - Espen E Spangenburg
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
| | - Steven J Prior
- University of Maryland School of Medicine and Baltimore Veterans Affairs Geriatric Research, Education and Clinical Center, Baltimore, Maryland
| | - James M Hagberg
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland;
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16
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Scheible KM, Emo J, Yang H, Holden-Wiltse J, Straw A, Huyck H, Misra S, Topham DJ, Ryan RM, Reynolds AM, Mariani TJ, Pryhuber GS. Developmentally determined reduction in CD31 during gestation is associated with CD8+ T cell effector differentiation in preterm infants. Clin Immunol 2015; 161:65-74. [PMID: 26232733 DOI: 10.1016/j.clim.2015.07.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 05/12/2015] [Accepted: 07/01/2015] [Indexed: 12/12/2022]
Abstract
Homeostatic T cell proliferation is more robust during human fetal development. In order to understand the relative effect of normal fetal homeostasis and perinatal exposures on CD8+ T cell behavior in PT infants, we characterized umbilical cord blood CD8+ T cells from infants born between 23-42weeks gestation. Subjects were recruited as part of the NHLBI-sponsored Prematurity and Respiratory Outcomes Program. Cord blood from PT infants had fewer naïve CD8+ T cells and lower regulatory CD31 expression on both naïve and effector, independent of prenatal exposures. CD8+ T cell in vitro effector function was greater at younger gestational ages, an effect that was exaggerated in infants with prior inflammatory exposures. These results suggest that CD8+ T cells earlier in gestation have loss of regulatory co-receptor CD31 and greater effector differentiation, which may place PT neonates at unique risk for CD8+ T cell-mediated inflammation and impaired T cell memory formation.
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Affiliation(s)
- Kristin M Scheible
- University of Rochester, Department of Pediatrics, 601 Elmwood Avenue, Rochester, NY 14642, United States.
| | - Jason Emo
- University of Rochester, Department of Pediatrics, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Hongmei Yang
- University of Rochester, Department of Biostatistics and Computational Biology, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Jeanne Holden-Wiltse
- University of Rochester, Department of Biostatistics and Computational Biology, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Andrew Straw
- University of Rochester, Department of Biostatistics and Computational Biology, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Heidie Huyck
- University of Rochester, Department of Pediatrics, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Sara Misra
- University of Rochester, Department of Pediatrics, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - David J Topham
- University of Rochester, Department of Microbiology and Immunology, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Rita M Ryan
- Medical University of South Carolina, Department of Pediatrics, Rutledge Tower, 135 Rutledge Avenue, Charleston, SC 29425, United States
| | - Anne Marie Reynolds
- State University of New York at Buffalo, Department of Pediatrics, 219 Bryant Street, Buffalo, NY 14222, United States
| | - Thomas J Mariani
- University of Rochester, Department of Pediatrics, 601 Elmwood Avenue, Rochester, NY 14642, United States; University of Rochester, Pediatric Molecular and Personalized Medicine Program, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Gloria S Pryhuber
- University of Rochester, Department of Pediatrics, 601 Elmwood Avenue, Rochester, NY 14642, United States
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17
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Saeidi A, Chong YK, Yong YK, Tan HY, Barathan M, Rajarajeswaran J, Sabet NS, Sekaran SD, Ponnampalavanar S, Che KF, Velu V, Kamarulzaman A, Larsson M, Shankar EM. Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8(+) T cells in HIV/TB co-infection. Cell Immunol 2015; 297:19-32. [PMID: 26071876 DOI: 10.1016/j.cellimm.2015.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 05/18/2015] [Accepted: 05/18/2015] [Indexed: 12/15/2022]
Abstract
The role of T-cell immunosenescence and functional CD8(+) T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of CD38, a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8(+) T cells. Up-regulation of CD57 and CD38 were directly proportional to lack of co-stimulatory markers on CD8(+) T cells, besides diminished expression of CD127 (IL-7Rα) on CD57(+)CD4(+) T cells. Notably, intracellular IFN-γ, perforin and granzyme B levels in HIV-specific CD8(+) T cells of HIV/TB co-infected subjects were diminished. Intracellular CD57 levels in HIV gag p24-specific CD8(+) T cells were significantly increased in HIV/TB co-infection. We suggest that HIV-TB co-infection contributes to senescence associated with chronic immune activation, which could be due to functional insufficiency of CD8(+) T cells.
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Affiliation(s)
- Alireza Saeidi
- Tropical Infectious Disease Research and Education Center (TIDREC), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Yee K Chong
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Yean K Yong
- Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Hong Y Tan
- Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Muttiah Barathan
- Tropical Infectious Disease Research and Education Center (TIDREC), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Jayakumar Rajarajeswaran
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Negar S Sabet
- Faculty of Medicine, SEGi University, Kota Damansara, 47810 Selangor, Malaysia
| | - Shamala D Sekaran
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Sasheela Ponnampalavanar
- Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Karlhans F Che
- Institute for Environmental Medicine, Karolinska Institute, Solna, 17 177 Stockholm, Sweden
| | - Vijayakumar Velu
- Department of Microbiology and Immunology, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA
| | - Adeeba Kamarulzaman
- Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Marie Larsson
- Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden
| | - Esaki M Shankar
- Tropical Infectious Disease Research and Education Center (TIDREC), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia; Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia; Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
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18
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Shankar EM, Velu V, Kamarulzaman A, Larsson M. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection. World J Virol 2015; 4:17-24. [PMID: 25674514 PMCID: PMC4308524 DOI: 10.5501/wjv.v4.i1.17] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/30/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023] Open
Abstract
Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis.
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19
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Abstract
Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.
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Affiliation(s)
- Costantino Iadecola
- Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA.
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20
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Larbi A, Fulop T. From "truly naïve" to "exhausted senescent" T cells: when markers predict functionality. Cytometry A 2013; 85:25-35. [PMID: 24124072 DOI: 10.1002/cyto.a.22351] [Citation(s) in RCA: 247] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Revised: 05/27/2013] [Accepted: 07/30/2013] [Indexed: 02/06/2023]
Abstract
The study of T cell biology has been accelerated by substantial progress at the technological level, particularly through the continuing advancement of flow cytometry. The conventional approach of observing T cells as either T helper or T cytotoxic is overly simplistic and does not allow investigators to clearly identify immune mechanisms or alterations in physiological processes that impact on clinical outcomes. The complexity of T cell sub-populations, as we understand them today, combined with the immunological and functional diversity of these subsets represent significant complications for the study of T cell biology. In this article, we review the use of classical markers in delineating T cell sub-populations, from "truly naïve" T cells (recent thymic emigrants with no proliferative history) to "exhausted senescent" T cells (poorly proliferative cells that display severe functional abnormalities) wherein the different phenotypes of these populations reflect their disparate functionalities. In addition, since persistent infections and chronological aging have been shown to be associated with significant alterations in human T cell distribution and function, we also discuss age-associated and cytomegalovirus-driven alterations in the expression of key subset markers.
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Affiliation(s)
- Anis Larbi
- Singapore Immunology Network (SIgN), Biopolis, Agency for Science Technology and Research (A*STAR), Singapore
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21
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Combined boyden-flow cytometry assay improves quantification and provides phenotypification of leukocyte chemotaxis. PLoS One 2011; 6:e28771. [PMID: 22174892 PMCID: PMC3235166 DOI: 10.1371/journal.pone.0028771] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 11/15/2011] [Indexed: 01/13/2023] Open
Abstract
Chemotaxis has been studied by classical methods that measure chemotactic and random motility responses in vitro, but these methods do not evaluate the total number and phenotype of migrating leukocytes simultaneously. Our objective was to develop and validate a novel assay, combined Boyden-flow cytometry chemotaxis assay (CBFCA), for simultaneous quantification and phenotypification of migrating leukocytes. CBFCA exhibited several important advantages in comparison to the classic Boyden chemotaxis assay (CBCA): 1) improved precision (intra-assay coefficients of variation (CVs): CBFCA-4.7 and 4.8% vs. CBCA-30.1 and 17.3%; inter-observer CVs: CBFCA-3.6% vs. CBCA 30.1%); 2) increased recovery of cells, which increased assay to provide increased sensitivity; 3) high specificity for determining the phenotype of migrating/attracted leukocytes; and 4) reduced performance time (CBFCA 120 min vs. CBCA 265 min). Other advantages of CBFCA are: 5) robustness, 6) linearity, 7) eliminated requirement for albumin and, importantly, 8) enabled recovery of migrating leukocytes for subsequent studies. This latter feature is of great benefit in the study of migrating leukocyte subsets. We conclude that the CBFCA is a novel and improved technique for experiments focused on understanding leukocyte trafficking during the inflammatory response.
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Rouhl RPW, Mertens AECS, van Oostenbrugge RJ, Damoiseaux JGMC, Debrus-Palmans LL, Henskens LHG, Kroon AA, de Leeuw PW, Lodder J, Tervaert JWC. Angiogenic T-cells and putative endothelial progenitor cells in hypertension-related cerebral small vessel disease. Stroke 2011; 43:256-8. [PMID: 21980212 DOI: 10.1161/strokeaha.111.632208] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND PURPOSE Cerebral small vessel disease (CSVD) may be caused by endothelial dysfunction, whereas endothelial progenitor cells (EPC) may attenuate endothelial dysfunction. Their vitality is lower in CSVD. A subset of lymphocytes, angiogenic T-cells, is capable to stimulate EPC function. The purpose of our study was to explore the relation between CSVD manifestations, angiogenic T-cells, and EPC in hypertensive patients with CSVD. METHODS We compared 32 essential hypertensive patients with CSVD (white matter lesions, asymptomatic lacunar infarcts, or microbleeds on 1.5-Tesla MRI) to 29 age-matched and sex-matched hypertensive controls. We counted angiogenic T-cells (CD3(+)/CD31(+)/CD184(+)) and putative EPC (CD31(+)/CD34(+)/CD45(-)/KDR(+)) by flow cytometry and determined EPC vitality by in vitro cluster formation. RESULTS Putative EPC numbers were lower in hypertensive individuals with CSVD than in those without (10±7(.)10(3)/mL versus 13±6(.)10(3)/mL [median±interquartile range]; P=0.011). Angiogenic T-cell numbers were also lower in hypertensive individuals with CSVD than in those without (0.56±0.25(.)10(9)/mL versus 0.78±0.50(.)10(9)/mL; P=0.008). Higher angiogenic T-cell numbers independently related to absence of CSVD (odds ratio, 0.088; 95% confidence interval, 0.012-0.627). CONCLUSIONS Our data suggest that angiogenic T-cells and putative EPC independently relate to radiological CSVD manifestations in hypertensive patients.
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Affiliation(s)
- Rob P W Rouhl
- Department of Neurology, Maastricht University Medical Centre, Maastricht, the Netherlands.
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Weil BR, Kushner EJ, Diehl KJ, Greiner JJ, Stauffer BL, Desouza CA. CD31+ T cells, endothelial function and cardiovascular risk. Heart Lung Circ 2011; 20:659-62. [PMID: 21767986 PMCID: PMC3176953 DOI: 10.1016/j.hlc.2011.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 06/17/2011] [Accepted: 06/19/2011] [Indexed: 11/25/2022]
Abstract
Deficits in endothelial cell repair mechanisms are thought to contribute to the aetiology of endothelial dysfunction and, subsequently, cardiovascular disease (CVD). CD31(+) T cells or so-called "angiogenic T cells" are a newly defined T cell subset that exhibit favourable vascular qualities and show a strong negative relation with atherosclerotic disease severity. Despite growing evidence that CD31(+) T cells are important for vascular homeostasis, it is currently unknown if CD31(+) T cell number and function are related to endothelial function and CVD risk in healthy adults. To address this question, we studied 24 healthy adult men (ages: 21-70). Endothelial function was assessed by the forearm blood flow (FBF) response to intra-arterial infusion of acetylcholine (ACh) and CVD risk was estimated by Framingham Risk Score (FRS). CD31(+) T cell number was determined by fluorescence-activated cell sorting. Magnetic-activated cell sorting was used to isolate CD31(+) T cells for Boyden chamber migration. No relation was observed between CD31(+) T cell number and FBF response to ACh or FRS. However, CD31(+) T cell migration to stromal cell-derived factor (SDF)-1α and vascular endothelial growth factor (VEGF) was positively correlated with FBF response to ACh (r = 0.43 for SDF-1α; r = 0.38 for VEGF; both P<0.05) and inversely related to FRS (r = -0.53 for SDF-1α; r = -0.48 for VEGF; both P<0.05). These findings demonstrate that CD31(+) T cell function, but not number, is associated with in vivo endothelial function and CVD risk in healthy adult men.
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Affiliation(s)
- Brian R Weil
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, CO 80309, USA
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Jenkins NT, Landers RQ, Prior SJ, Soni N, Spangenburg EE, Hagberg JM. Effects of acute and chronic endurance exercise on intracellular nitric oxide and superoxide in circulating CD34⁺ and CD34⁻ cells. J Appl Physiol (1985) 2011; 111:929-37. [PMID: 21700895 DOI: 10.1152/japplphysiol.00541.2011] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
We investigated the influence of acute and chronic endurance exercise on levels of intracellular nitric oxide (NO), superoxide (O₂·⁻), and expression of genes regulating the balance between these free radicals in CD34⁺ and CD34⁻ peripheral blood mononuclear cells (PBMCs; isolated by immunomagnetic cell separation). Blood samples were obtained from age- and body mass index (BMI)-matched endurance-trained (n = 10) and sedentary (n = 10) men before and after 30 min of exercise at 75% maximal oxygen uptake (·VO(₂max)). Baseline levels of intracellular NO (measured by DAF-FM diacetate) and O₂·⁻ (measured by dihydroethidium) were 26% (P < 0.05) and 10% (P < 0.05) higher, respectively, in CD34⁺ PBMCs from the sedentary group compared with the endurance-trained group. CD34⁺ PBMCs from the sedentary group at baseline had twofold greater inducible nitric oxide synthase (iNOS) mRNA and 50% lower endothelial NOS (eNOS) mRNA levels compared with the trained group (P < 0.05). The baseline group difference in O₂·⁻ was eliminated by acute exercise. Experiments with apocynin indicated that the training-related difference in O₂·⁻ levels was explained by increased NADPH oxidase activity in the sedentary state. mRNA levels of additional angiogenic and antioxidant genes were consistent with a more angiogenic profile in CD34⁺ cells of trained subjects. CD34⁻ PBMCs, examined for exploratory purposes, also displayed a more angiogenic mRNA profile in trained subjects, with vascular endothelial growth factor (VEGF) and eNOS being more highly expressed in trained subjects. Overall, our data suggest an association between the sedentary state and increased nitro-oxidative stress in CD34⁺ cells.
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Ludlow AT, Roth SM. Physical activity and telomere biology: exploring the link with aging-related disease prevention. J Aging Res 2011; 2011:790378. [PMID: 21403893 PMCID: PMC3043290 DOI: 10.4061/2011/790378] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 12/18/2010] [Accepted: 12/30/2010] [Indexed: 11/20/2022] Open
Abstract
Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and an aged phenotype. Several reports have recently associated telomeres and telomere-related proteins to diseases associated with physical inactivity and aging including cardiovascular disease, insulin resistance, and hypertension. Interestingly several reports have also shown that longer telomeres are associated with higher physical activity levels, indicating a potential mechanistic link between physical activity, reduced age-related disease risk, and longevity. The primary purpose of this review is to discuss the potential importance of physical activity in telomere biology in the context of inactivity- and age-related diseases. A secondary purpose is to explore potential mechanisms and important avenues for future research in the field of telomeres and diseases associated with physical inactivity and aging.
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Affiliation(s)
- Andrew T Ludlow
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742-2611, USA
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