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Ramírez-Cruz A, Rios-Lugo MJ, Soto-Sánchez J, Juárez-Pérez CA, Cabello-López A, Jiménez-Ramírez C, Chang-Rueda C, Cruz M, Hernández-Mendoza H, Vazquez-Moreno M. Overweight, Obesity, Hypertriglyceridemia, and Insulin Resistance Are Positively Associated with High Serum Copper Levels in Mexican Adults. Metabolites 2024; 14:282. [PMID: 38786759 PMCID: PMC11122773 DOI: 10.3390/metabo14050282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/27/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024] Open
Abstract
Recently, the role of trace elements in the pathophysiology of obesity, insulin resistance (IR), and metabolic diseases has been explored. In this cross-sectional study, we aimed to assess the association of overweight, obesity, and cardiometabolic traits with serum copper (Cu) levels in 346 Mexican adults. Serum Cu level was measured by inductively coupled plasma mass spectrometry (ICP-MS). Anthropometrical data were collected, and biochemical parameters were measured. The triglyceride-glucose (TyG) index was used as a surrogate marker to evaluate IR. Overweight and obesity status was positively associated with the serum Cu level (β = 19.434 ± 7.309, p = 0.008). Serum Cu level was observed to have a positive association with serum triglycerides level (β = 0.160 ± 0.045, p < 0.001) and TyG (β = 0.001 ± 0.001, p < 0.001). Additionally, high serum Cu level was positively associated with overweight and obesity status (odds ratio [OR] = 1.9, 95% confidence interval [95% CI] 1.1-3.4, p = 0.014), hypertriglyceridemia (OR = 3.0, 95% CI 1.7-5.3, p < 0.001), and IR (OR = 2.6, 95% CI 1.4-4.6, p = 0.001). In conclusion, our results suggest that overweight, obesity, hypertriglyceridemia, and IR are positively associated with serum Cu levels in Mexican adults.
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Affiliation(s)
- Armando Ramírez-Cruz
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico; (A.R.-C.)
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Ciudad de México 09340, Mexico
| | - María Judith Rios-Lugo
- Facultad de Enfermería y Nutrición, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78290, Mexico;
- Sección de Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, Mexico
| | - Jacqueline Soto-Sánchez
- Sección de Estudios de Posgrado e Investigación, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México 07320, Mexico
| | - Cuauhtémoc Arturo Juárez-Pérez
- Unidad de Investigación de Salud en el Trabajo, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
| | - Alejandro Cabello-López
- Unidad de Investigación de Salud en el Trabajo, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
| | - Carmina Jiménez-Ramírez
- Unidades Médicas de Alta Especialidad, Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, Ciudad de México 07760, Mexico
| | - Consuelo Chang-Rueda
- Facultad de Ciencias Químicas, Campus IV, Universidad Autónoma de Chiapas, Tapachula 30792, Mexico
| | - Miguel Cruz
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico; (A.R.-C.)
| | - Héctor Hernández-Mendoza
- Instituto de Investigación de Zonas Desérticas, Universidad Autónoma de San Luis Potosí, Altair 200, San Luís Potosí 78377, Mexico
- Laboratorio del Agua y Monitoreo Ambiental, Universidad del Centro de México, San Luis Potosí 78250, Mexico
| | - Miguel Vazquez-Moreno
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico; (A.R.-C.)
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Christakoudi S, Tsilidis KK, Evangelou E, Riboli E. Sex differences in the associations of body size and body shape with platelets in the UK Biobank cohort. Biol Sex Differ 2023; 14:12. [PMID: 36814334 PMCID: PMC9945692 DOI: 10.1186/s13293-023-00494-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 02/08/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Obesity is accompanied by low-grade inflammation and leucocytosis and increases the risk of venous thromboembolism. Associations with platelet count, however, are unclear, because several studies have reported positive associations only in women. Associations with body shape are also unclear, because waist and hip circumferences reflect overall body size, as well as body shape, and are correlated strongly positively with body mass index (BMI). METHODS We evaluated body shape with the allometric body shape index (ABSI) and hip index (HI), which reflect waist and hip size among individuals with the same weight and height and are uncorrelated with BMI. We examined the associations of BMI, ABSI, and HI with platelet count, mean platelet volume (MPV), and platelet distribution width (PDW) in multivariable linear regression models for 125,435 UK Biobank women and 114,760 men. We compared men with women, post-menopausal with pre-menopausal women, and older (≥ 52 years) with younger (< 52 years) men. RESULTS BMI was associated positively with platelet count in women, more strongly in pre-menopausal than in post-menopausal, and weakly positively in younger men but strongly inversely in older men. Associations of BMI with platelet count were shifted towards the inverse direction for daily alcohol consumption and current smoking, resulting in weaker positive associations in women and stronger inverse associations in men, compared to alcohol ≤ 3 times/month and never smoking. BMI was associated inversely with MPV and PDW in pre-menopausal women but positively in post-menopausal women and in men. ABSI was associated positively with platelet count, similarly in women and men, while HI was associated weakly inversely only in women. ABSI was associated inversely and HI positively with MPV but not with PDW and only in women. Platelet count was correlated inversely with platelet size and positively with leucocyte counts, most strongly with neutrophils. CONCLUSIONS Competing factors determine the associations of BMI with platelet count. Factors with sexually dimorphic action (likely thrombopoietin, inflammatory cytokines, or cortisol), contribute to a positive association, more prominently in women than in men, while age-dependent factors (likely related to liver damage and fibrosis), contribute to an inverse association, more prominently in men than in women.
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Affiliation(s)
- Sofia Christakoudi
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK. .,Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK.
| | - Konstantinos K. Tsilidis
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place, London, W2 1PG UK ,grid.9594.10000 0001 2108 7481Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Evangelos Evangelou
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place, London, W2 1PG UK ,grid.9594.10000 0001 2108 7481Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Elio Riboli
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place, London, W2 1PG UK
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Urao N, Liu J, Takahashi K, Ganesh G. Hematopoietic Stem Cells in Wound Healing Response. Adv Wound Care (New Rochelle) 2022; 11:598-621. [PMID: 34353116 PMCID: PMC9419985 DOI: 10.1089/wound.2021.0065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Significance: Emerging evidence has shown a link between the status of hematopoietic stem cells (HSCs) and wound healing responses. Thus, better understanding HSCs will contribute to further advances in wound healing research. Recent Advances: Myeloid cells such as neutrophils and monocyte-derived macrophages are critical players in the process of wound healing. HSCs actively respond to wound injury and other tissue insults, including infection and produce the effector myeloid cells, and a failing of the HSC response can result in impaired wound healing. Technological advances such as transcriptome at single-cell resolution, epigenetics, three-dimensional imaging, transgenic animals, and animal models, have provided novel concepts of myeloid generation (myelopoiesis) from HSCs, and have revealed cell-intrinsic and -extrinsic mechanisms that can impact HSC functions in the context of health conditions. Critical Issues: The newer concepts include-the programmed cellular fate at a differentiation stage that is used to be considered as the multilineage, the signaling pathways that can activate HSCs directly and indirectly, the mechanisms that can deteriorate HSCs, the roles and remodeling of the surrounding environment for HSCs and their progenitors (the niche). Future Directions: The researches on HSCs, which produce blood cells, should contribute to the development of blood biomarkers predicting a risk of chronic wounds, which may transform clinical practice of wound care with precision medicine for patients at high risk of poor healing.
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Affiliation(s)
- Norifumi Urao
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA.,Correspondence: Department of Pharmacology, State University of New York Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Room 5322, Syracuse, NY 13210, USA.
| | - Jinghua Liu
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Kentaro Takahashi
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Gayathri Ganesh
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA
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Birulina JG, Voronkova OV, Ivanov VV, Buyko EE, Shcherbakova MM, Chernyshov NA, Motlokhova EA. Systemic inflammation markers of diet-induced metabolic syndrome in rat model. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2022. [DOI: 10.24075/brsmu.2022.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Chronic systemic inflammation is essential in many chronic non-infectious diseases, including type 2 diabetes, obesity and metabolic syndrome (MS). This study aimed at characterization of systemic inflammatory reaction as a component of diet-induced MS in rat model. Thirty-three male Wistar rats were distributed into two groups designated 'control' (n = 15) and 'experimental (MS)' (n = 18). The groups were fed, respectively, regular and high-fat/high-carbohydrate diets for 12 weeks. The intensity of systemic inflammatory process against the background of metabolic impairments was assessed by total and differential counts of white blood cells and serum levels of total protein, C-reactive protein, cytokines (IL6, IL10 and TNFα), insulin and leptin. We also assessed the production of reactive oxygen species in adipose tissue samples. The experiment revealed signs of systemic inflammation in MS as compared to control, including reactive leukocytosis, hyperproteinemia and increased serum levels of C-reactive protein (2.6-fold; р = 0.001), IL10 (3.7-fold; р = 0.029) and TNFα (4.2-fold; р = 0.035). The observed changes were accompanied by elevated metabolic activity of visceral adipose tissue, indicated by hyperleptinemia and increased free radical oxidation intensity. Pairwise positive correlations of serum levels were revealed for leptin and insulin (r = 0.701; р = 0.001) and leptin and IL10 (r = 0.523; р = 0.012). Thus, high-fat/ high-carbohydrate diet promoted metabolic impairments concomitantly with early signs of systemic inflammation characteristic of MS and obesity.
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Affiliation(s)
- JG Birulina
- Siberian State Medical University, Tomsk, Russia
| | - OV Voronkova
- Siberian State Medical University, Tomsk, Russia
| | - VV Ivanov
- Siberian State Medical University, Tomsk, Russia
| | - EE Buyko
- Siberian State Medical University, Tomsk, Russia
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Serum Proteomic Analysis of Cannabis Use Disorder in Male Patients. Molecules 2021; 26:molecules26175311. [PMID: 34500744 PMCID: PMC8434053 DOI: 10.3390/molecules26175311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 12/18/2022] Open
Abstract
Cannabis use has been growing recently and it is legally consumed in many countries. Cannabis has a variety of phytochemicals including cannabinoids, which might impair the peripheral systems responses affecting inflammatory and immunological pathways. However, the exact signaling pathways that induce these effects need further understanding. The objective of this study is to investigate the serum proteomic profiling in patients diagnosed with cannabis use disorder (CUD) as compared with healthy control subjects. The novelty of our study is to highlight the differentially changes proteins in the serum of CUD patients. Certain proteins can be targeted in the future to attenuate the toxicological effects of cannabis. Blood samples were collected from 20 male individuals: 10 healthy controls and 10 CUD patients. An untargeted proteomic technique employing two-dimensional difference in gel electrophoresis coupled with mass spectrometry was employed in this study to assess the differentially expressed proteins. The proteomic analysis identified a total of 121 proteins that showed significant changes in protein expression between CUD patients (experimental group) and healthy individuals (control group). For instance, the serum expression of inactive tyrosine protein kinase PEAK1 and tumor necrosis factor alpha-induced protein 3 were increased in CUD group. In contrast, the serum expression of transthyretin and serotransferrin were reduced in CUD group. Among these proteins, 55 proteins were significantly upregulated and 66 proteins significantly downregulated in CUD patients as compared with healthy control group. Ingenuity pathway analysis (IPA) found that these differentially expressed proteins are linked to p38MAPK, interleukin 12 complex, nuclear factor-κB, and other signaling pathways. Our work indicates that the differentially expressed serum proteins between CUD and control groups are correlated to liver X receptor/retinoid X receptor (RXR), farnesoid X receptor/RXR activation, and acute phase response signaling.
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Purdy JC, Shatzel JJ. The hematologic consequences of obesity. Eur J Haematol 2020; 106:306-319. [PMID: 33270290 DOI: 10.1111/ejh.13560] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/28/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022]
Abstract
The prevalence of obesity is increasing and progressively influencing physician-patient interactions. While there is a sizable amount of data demonstrating that obesity is a state of low-grade inflammation, to our knowledge, there is no single review summarizing its effects on hematologic parameters and thrombotic risk. We performed a literature search which largely surfaced observational studies, with a few systematic reviews and meta-analyses of these studies. We took care to review the mechanisms driving an inflammatory state and obesity's effect on white blood cells, red blood cells, platelets, and thrombotic risk. There is an observed relative, and sometimes absolute leukocytosis driven by this inflammatory state. Obesity is also associated with increased platelet counts and an increased risk for venous thromboembolism (VTE). Lastly, the association between obesity, iron deficiency (ID), and red blood cell counts may be present but remains uncertain. Recognizing the above associations may provide clinicians with reassurance regarding otherwise unexplained hematologic abnormalities in obese individuals. We hope this review will prompt future studies to further understand the underlying mechanisms driving these abnormalities and identify modifiable risk factors and potential therapeutic targets to prevent the development of probable obesity-associated conditions with significant morbidity and mortality, such as ID and VTE.
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Affiliation(s)
- Johanna C Purdy
- Division of General Internal Medicine and Geriatrics, Oregon Health & Science University, Portland, OR, USA
| | - Joseph J Shatzel
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA.,Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
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Alasmari F, Alsanea S, Masood A, Alhazzani K, Alanazi IO, Musambil M, Alfadda AA, Alshammari MA, Alasmari AF, Benabdelkamel H. Serum proteomic profiling of patients with amphetamine use disorder. Drug Alcohol Depend 2020; 214:108157. [PMID: 32652378 DOI: 10.1016/j.drugalcdep.2020.108157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/22/2020] [Accepted: 06/23/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Amphetamine use disorder has been recently classified as an epidemic condition. Amphetamine use/abuse has been associated with several neurological and inflammatory effects. However, the exact mechanism involved in these effects warrants further investigation. The aim of this study was to determine any alterations in the serum proteome of individuals classified as patients with amphetamine use disorder compared to that of control subjects. METHODS An untargeted proteomic approach employing two-dimensional difference in gel electrophoresis coupled with mass spectrometry was used to identify the patterns of differentially expressed proteins. Serum samples were collected from 20 individuals (males) including 10 subjects with amphetamine use disorder and 10 healthy controls for the present study. RESULTS The analysis revealed 78 proteins with a significant difference in protein abundance between the amphetamine-addicted subjects and controls. Among them, 71 proteins were upregulated while 7 proteins remained downregulated in the amphetamine-addicted group. These proteins were further analyzed by ingenuity pathway analysis (IPA) to investigate their correlation with other biomarkers. IPA revealed the correlation of altered proteins with mitogen-activated protein kinase (MAP2K1/K2), p38MAPK, protein kinase-B (PKB; Akt), extracellular signal-regulated kinase (ERK1/2), and nuclear factor-κB signaling pathways. Importantly, these pathways are highly involved in neurological diseases, inflammatory responses, and cellular compromise. CONCLUSIONS Our data suggest that the changes in the levels of serum proteins between amphetamine and control groups might affect cellular compromise, inflammatory response, and neurological diseases.
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Affiliation(s)
- Fawaz Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Sary Alsanea
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Afshan Masood
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia
| | - Khalid Alhazzani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Ibrahim O Alanazi
- The National Center of Biotechnology (NCB), Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), P.O. Box 6086, Riyadh, Saudi Arabia
| | - Mohthash Musambil
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia
| | - Assim A Alfadda
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia; Department of Medicine, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia
| | - Musaad A Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Abdullah F Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Hicham Benabdelkamel
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia.
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Yang Y, Yin R, Wu R, Ramirez CN, Sargsyan D, Li S, Wang L, Cheng D, Wang C, Hudlikar R, Kuo HC, Lu Y, Kong AN. DNA methylome and transcriptome alterations and cancer prevention by triterpenoid ursolic acid in UVB-induced skin tumor in mice. Mol Carcinog 2019; 58:1738-1753. [PMID: 31237383 PMCID: PMC6722003 DOI: 10.1002/mc.23046] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 05/02/2019] [Accepted: 05/06/2019] [Indexed: 12/11/2022]
Abstract
Nonmelanoma skin cancers (NMSCs) are the most common type of skin cancers. Major risk factors for NMSCs include exposure to ultraviolet (UV) irradiation. Ursolic acid (UA) is a natural triterpenoid enriched in blueberries and herbal medicinal products, and possess anticancer activities. This study focuses on the impact of UA on epigenomic, genomic mechanisms and prevention of UVB-mediated NMSC. CpG methylome and RNA transcriptome alterations of early, promotion and late stages of UA treated on UVB-induced NMSC in SKH-1 hairless mice were conducted using CpG methyl-seq and RNA-seq. Samples were collected at weeks 2, 15, and 25, and integrated bioinformatic analyses were performed to identify key pathways and genes modified by UA against UVB-induced NMSC. Morphologically, UA significantly reduced NMSC tumor volume and tumor number. DNA methylome showed inflammatory pathways IL-8, NF-κB, and Nrf2 pathways were highly involved. Antioxidative stress master regulator Nrf2, cyclin D1, DNA damage, and anti-inflammatory pathways were induced by UA. Nrf2, cyclin D1, TNFrsf1b, and Mybl1 at early (2 weeks) and late (25 weeks) stages were identified and validated by quantitative polymerase chain reaction. In summary, integration of CpG methylome and RNA transcriptome studies show UA alters antioxidative, anti-inflammatory, and anticancer pathways in UVB-induced NMSC carcinogenesis. Particularly, UA appears to drive Nrf2 and its upstream/downstream genes, anti-inflammatory (at early stages) and cell cycle regulatory (both early and late stages) genes, of which might contribute to the overall chemopreventive effects of UVB-induced MNSC. This study may provide potential biomarkers/targets for chemoprevention of early stage of UVB-induced NMSC in human.
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Affiliation(s)
- Yuqing Yang
- Graduate Program in Pharmaceutical Science, Ernest Mario
School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ
08854, USA
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Ran Yin
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Christina N. Ramirez
- Center for Phytochemicals Epigenome Studies, Ernest Mario
School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ
08854, USA
- Cellular and Molecular Pharmacology Program, Rutgers Robert
Wood Johnson Medical School, Piscataway, NJ 08854, USA
| | - Davit Sargsyan
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Shanyi Li
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Lujing Wang
- Graduate Program in Pharmaceutical Science, Ernest Mario
School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ
08854, USA
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - David Cheng
- Graduate Program in Pharmaceutical Science, Ernest Mario
School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ
08854, USA
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Chao Wang
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Rasika Hudlikar
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Hsiao-Chen Kuo
- Graduate Program in Pharmaceutical Science, Ernest Mario
School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ
08854, USA
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Yaoping Lu
- Center for Phytochemicals Epigenome Studies, Ernest Mario
School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ
08854, USA
- Department of Chemical Biology, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
USA
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Daher R, Lefebvre T, Puy H, Karim Z. Extrahepatic hepcidin production: The intriguing outcomes of recent years. World J Clin Cases 2019; 7:1926-1936. [PMID: 31423425 PMCID: PMC6695539 DOI: 10.12998/wjcc.v7.i15.1926] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023] Open
Abstract
Hepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.
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Affiliation(s)
- Raêd Daher
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Thibaud Lefebvre
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Hervé Puy
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Zoubida Karim
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
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Fernández-Gayol O, Sanchis P, Aguilar K, Navarro-Sempere A, Comes G, Molinero A, Giralt M, Hidalgo J. Different Responses to a High-Fat Diet in IL-6 Conditional Knockout Mice Driven by Constitutive GFAP-Cre and Synapsin 1-Cre Expression. Neuroendocrinology 2019; 109:113-130. [PMID: 30636247 DOI: 10.1159/000496845] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 01/12/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS Interleukin-6 (IL-6) is a major cytokine controlling body weight and metabolism, at least in part through actions in the central nervous system (CNS) from local sources. METHODS We herewith report results obtained in conditional IL-6 KO mice for brain cells (Il6ΔGfap and Il6ΔSyn). RESULTS The reporter RiboTag mouse line demonstrated specific astrocytic expression of GFAP-dependent Cre in the hypothalamus but not in other brain areas, whereas that of synapsin 1-dependent Cre was specific for neurons. Feeding a high-fat diet (HFD) or a control diet showed that Il6ΔGfap and Il6ΔSyn mice were more prone and resistant, respectively, to HFD-induced obesity. Energy intake was not altered in HFD experiments, but it was reduced in Il6ΔSyn male mice following a 24-h fast. HFD increased circulating insulin, leptin, and cholesterol levels, decreased triglycerides, and caused impaired responses to the insulin and glucose tolerance tests. In Il6ΔGfap mice, the only significant difference observed was an increase in insulin levels of females, whereas in Il6ΔSyn mice the effects of HFD were decreased. Hypothalamic Agrp expression was significantly decreased by HFD, further decreased in Il6ΔGfap, and increased in Il6ΔSyn female mice. Hypothalamic Il-6 mRNA levels were not decreased in Il6ΔSyn mice and even increased in Il6ΔGfapmale mice. Microarray analysis of hypothalamic RNA showed that female Il6ΔGfap mice had increased interferon-related pathways and affected processes in behavior, modulation of chemical synaptic transmission, learning, and memory. CONCLUSION The present results demonstrate that brain production of IL-6 regulates body weight in the context of caloric excess and that the cellular source is critical.
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Affiliation(s)
- Olaya Fernández-Gayol
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Paula Sanchis
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Kevin Aguilar
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alicia Navarro-Sempere
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Gemma Comes
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Amalia Molinero
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Mercedes Giralt
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Juan Hidalgo
- Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain,
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11
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Udit S, Burton M, Rutkowski JM, Lee S, Bookout AL, Scherer PE, Elmquist JK, Gautron L. Na v1.8 neurons are involved in limiting acute phase responses to dietary fat. Mol Metab 2017; 6:1081-1091. [PMID: 29031710 PMCID: PMC5641637 DOI: 10.1016/j.molmet.2017.07.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 07/19/2017] [Accepted: 07/24/2017] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE AND METHODS Metabolic viscera and their vasculature are richly innervated by peripheral sensory neurons. Here, we examined the metabolic and inflammatory profiles of mice with selective ablation of all Nav1.8-expressing primary afferent neurons. RESULTS While mice lacking sensory neurons displayed no differences in body weight, food intake, energy expenditure, or body composition compared to controls on chow diet, ablated mice developed an exaggerated inflammatory response to high-fat feeding characterized by bouts of weight loss, splenomegaly, elevated circulating interleukin-6 and hepatic serum amyloid A expression. This phenotype appeared to be directly mediated by the ingestion of saturated lipids. CONCLUSIONS These data demonstrate that the Nav1.8-expressing afferent neurons are not essential for energy balance but are required for limiting the acute phase response caused by an obesogenic diet.
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Affiliation(s)
- Swalpa Udit
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Michael Burton
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Joseph M Rutkowski
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Syann Lee
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Angie L Bookout
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA
| | - Joel K Elmquist
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA.
| | - Laurent Gautron
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas 75390, TX, USA.
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12
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Rubinow KB, Rubinow DR. In immune defense: redefining the role of the immune system in chronic disease. DIALOGUES IN CLINICAL NEUROSCIENCE 2017. [PMID: 28566944 PMCID: PMC5442360 DOI: 10.31887/dcns.2017.19.1/drubinow] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The recognition of altered immune system function in many chronic disease states has proven to be a pivotal advance in biomedical research over the past decade. For many metabolic and mood disorders, this altered immune activity has been characterized as inflammation, with the attendant assumption that the immune response is aberrant. However, accumulating evidence challenges this assumption and suggests that the immune system may be mounting adaptive responses to chronic stressors. Further, the inordinate complexity of immune function renders a simplistic, binary model incapable of capturing critical mechanistic insights. In this perspective article, we propose alternative paradigms for understanding the role of the immune system in chronic disease. By invoking allostasis or systems biology rather than inflammation, we can ascribe greater functional significance to immune mediators, gain newfound appreciation of the adaptive facets of altered immune activity, and better avoid the potentially disastrous effects of translating erroneous assumptions into novel therapeutic strategies.
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Affiliation(s)
- Katya B Rubinow
- Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - David R Rubinow
- Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA
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13
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Lana JP, Martins LB, Oliveira MCD, Menezes-Garcia Z, Yamada LTP, Vieira LQ, Teixeira MM, Ferreira AVM. TNF and IL-18 cytokines may regulate liver fat storage under homeostasis conditions. Appl Physiol Nutr Metab 2017; 41:1295-1302. [PMID: 27863204 DOI: 10.1139/apnm-2016-0265] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The inflammation induced by obesogenic diets is associated with deposition of fat in the liver. On the other hand, anti-inflammatory and immunosuppressive therapies may impact in body fat storage and in liver lipid dynamics. It is important to study specific inflammatory mediators in this context, since their role on hepatic damage is not fully clarified. This study aimed to evaluate the role of interleukin (IL)-18 and tumor necrosis factor (TNF) receptor in liver dysfunction induced by diet. Male C57BL/6 wild-type (WT), IL-18, and TNF receptor 1 knockout mice (IL-18-/- and TNFR1-/-) were divided according to the experimental diets: chow diet or a high-refined carbohydrate-containing diet. Alanine aminotransferase was quantified by colorimetric analysis. Total fat content in the liver was determined by Folch methods. Levels of TNF, IL-6, IL-4, and IL-13 in liver samples were measured by ELISA assay. IL-18 and TNFR knockout mice fed with chow diet showed higher liver triglycerides deposition than WT mice fed with the same diet (WT: 131.9 ± 24.5; IL-18-/-: 239.4 ± 38.12*; TNF-/-: 179.6 ± 50.45*; *P < 0.01). Furthermore, these animals also showed a worse liver histopathological score and lower levels of TNF, IL-6, IL-4, and IL-13 in the liver. Interestingly, treatment with a high-carbohydrate diet did not exacerbate liver damage in IL-18-/- and TNFR1-/- mice. Our data suggest that IL-18 and TNF may be involved on hepatic homeostasis mainly in a context of a healthy diet.
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Affiliation(s)
- Jaqueline Pereira Lana
- a Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,b Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Laís Bhering Martins
- a Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,b Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marina Chaves de Oliveira
- a Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,b Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Zélia Menezes-Garcia
- b Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Leda Quercia Vieira
- b Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Mauro Martins Teixeira
- b Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Adaliene Versiani Matos Ferreira
- a Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,b Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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14
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Iizuka D, Yoshioka S, Kawai H, Okazaki E, Kiriyama K, Izumi S, Nishimura M, Shimada Y, Kamiya K, Suzuki F. Hepcidin-2 in mouse urine as a candidate radiation-responsive molecule. JOURNAL OF RADIATION RESEARCH 2016; 57:142-9. [PMID: 26826199 PMCID: PMC4795955 DOI: 10.1093/jrr/rrv098] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 10/26/2015] [Accepted: 11/06/2015] [Indexed: 05/24/2023]
Abstract
We used high-performance liquid chromatography to separate urine obtained from whole-body gamma-irradiated mice (4 Gy) before analyzing each fraction with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to identify radiation-responsive molecules. We identified two candidates: hepcidin antimicrobial peptide 2 (hepcidin-2) and peptide fragments of kidney androgen-regulated protein (KAP). We observed that peak increases of hepcidin-2 in urine were delayed in a dose-dependent manner (1 Gy and above); however, the amount of KAP peptide fragments showed no correlation with radiation dose. In addition, an increase in hepcidin-2 after exposure to relatively low radiation doses (0.25 and 0.5 Gy, respectively) was biphasic (at 8-48 h and 120-168 h, respectively, after irradiation). The increase in hepcidin-2 paralleled an increase in hepcidin-2 gene (Hamp2) mRNA levels in the liver. These results suggest that radiation exposure directly or indirectly induces urinary excretion of hepcidin-2 at least in part by the upregulation of Hamp2 mRNA in the liver.
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Affiliation(s)
- Daisuke Iizuka
- Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
| | - Susumu Yoshioka
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8511, Japan
| | - Hidehiko Kawai
- Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
| | - Emi Okazaki
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8511, Japan
| | - Keita Kiriyama
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8511, Japan
| | - Shunsuke Izumi
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8511, Japan
| | - Mayumi Nishimura
- Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555, Japan
| | - Yoshiya Shimada
- Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555, Japan
| | - Kenji Kamiya
- Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Fumio Suzuki
- Department of International Radiation Emergency Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
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15
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Expression of α1-acid glycoprotein and lipopolysaccharide binding protein in visceral and subcutaneous adipose tissue of dairy cattle. Vet J 2015; 203:223-7. [DOI: 10.1016/j.tvjl.2014.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Revised: 11/30/2014] [Accepted: 12/01/2014] [Indexed: 11/21/2022]
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Abstract
Obesity markedly increases susceptibility to a range of diseases and simultaneously undermines the viability and fate selection of haematopoietic stem cells (HSCs), and thus the kinetics of leukocyte production that is critical to innate and adaptive immunity. Considering that blood cell production and the differentiation of HSCs and their progeny is orchestrated, in part, by complex interacting signals emanating from the bone marrow microenvironment, it is not surprising that conditions that disturb bone marrow structure inevitably disrupt both the numbers and lineage-fates of these key blood cell progenitors. In addition to the increased adipose burden in visceral and subcutaneous compartments, obesity causes a marked increase in the size and number of adipocytes encroaching into the bone marrow space, almost certainly disturbing HSC interactions with neighbouring cells, which include osteoblasts, osteoclasts, mesenchymal cells and endothelial cells. As the global obesity pandemic grows, the short-term and long-term consequences of increased bone marrow adiposity on HSC lineage selection and immune function remain uncertain. This Review discusses the differentiation and function of haematopoietic cell populations, the principal physicochemical components of the bone marrow niche, and how this environment influences HSCs and haematopoiesis in general. The effect of adipocytes and adiposity on HSC and progenitor cell populations is also discussed, with the goal of understanding how obesity might compromise the core haematopoietic system.
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Affiliation(s)
- Benjamin J Adler
- Department of Biomedical Engineering, Bioengineering Building, Stony Brook University, Stony Brook, NY 11794-5281, USA
| | - Kenneth Kaushansky
- Department of Medicine, Health Sciences Centre, Stony Brook University, Stony Brook, NY 11794-8430, USA
| | - Clinton T Rubin
- Department of Biomedical Engineering, Bioengineering Building, Stony Brook University, Stony Brook, NY 11794-5281, USA
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17
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Gotardo ÉMF, dos Santos AN, Miyashiro RA, Gambero S, Rocha T, Ribeiro ML, Gambero A. Mice that are fed a high-fat diet display increased hepcidin expression in adipose tissue. J Nutr Sci Vitaminol (Tokyo) 2014; 59:454-61. [PMID: 24418880 DOI: 10.3177/jnsv.59.454] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Since the discovery that hepcidin is expressed in the adipose tissue of obese subjects, attention has been increasingly focused on alterations in iron homeostasis that are associated with adiposity. We examined the production of hepcidin, the expression of hepcidin-related genes and the iron content of the adipose tissue in obesity using Swiss mice fed a high-fat diet (HFD). The mice were maintained on a control diet or HFD for 12 or 24 wk, and body weight, adiposity and glucose homeostasis were evaluated. The expression of several genes (hepcidin, TfR1, TfR2, DMT1, FT-heavy, ferroportin, IRP-1, IRP-2 and HIF-1) and the protein expression of hepcidin and IL-6 were quantified. The iron level was assessed using a Prussian blue reaction in paraffin-embedded tissue. After 24 wk on the HFD, we observed increases in the levels of hepcidin in the serum and the visceral adipose tissue. The IL-6 levels also increased in the visceral adipose tissue. Adipocytes isolated from the visceral adipose tissues of lean and obese mice expressed hepcidin at comparable levels; however, isolated macrophages from the stromal vascular fraction expressed higher hepcidin levels. Adipose tissues from obese mice displayed increased tfR2 expression and the presence of iron. Our results indicate that IL-6 and iron may affect the signaling pathways governing hepcidin expression. Thus, the mice fed HFD for 24 wk represent a suitable model for the study of obesity-linked hepcidin alterations. In addition, hepcidin may play local roles in controlling iron availability and interfering with inflammation in adipose tissue.
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18
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LC-MS/MS analysis of visceral and subcutaneous adipose tissue proteomes in young goats with focus on innate immunity and inflammation related proteins. J Proteomics 2014; 108:295-305. [PMID: 24911890 DOI: 10.1016/j.jprot.2014.05.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 05/27/2014] [Accepted: 05/28/2014] [Indexed: 11/22/2022]
Abstract
UNLABELLED The endocrine role of adipose tissue and its involvement in several physiological and pathological processes are well recognized. Studies on human, mouse and rat adipose tissues have made clear that subcutaneous and visceral deposits play different roles, which is also reflected by different protein and gene expression patterns. In ruminants, fat tissues play important biological roles not only for animal health, but also for quality and gain in meat and milk production. Yet very few studies have explored the ruminant adipose tissue proteomes. The aim of our study was to compare subcutaneous and visceral adipose tissues of goat, focusing on proteins involved in immune and inflammatory response. A 2-D LC-MS/MS approach followed by cluster analysis shows a clear distinction between subcutaneous and visceral fat tissue proteomes, and qualitative RT-PCR based analysis of 30 potential adipokines further confirmed the individual expression patterns of 26 of these, including 7 whose mRNA expression was observed for the first time in adipose tissues. This study provides a first description of adipose tissue proteomes in goat, and presents observations on novel proteins related to metabolic and inflammatory pathways. The mass spectrometry data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD000564. BIOLOGICAL SIGNIFICANCE The proteomic analysis of different subcutaneous and visceral adipose tissue deposits showed tissue specific differences in protein expressions of well known as well as novel adipokines. This highlights the importance of sampling site when studying adipose tissue's metabolic roles. The protein expression characteristics of adipose tissues was evaluated by quantitative RT-PCR, and confirmed that adipose tissues play a central role in controlling inflammation, detoxification and coagulation pathways, as well as regulation of body fat mobilization in dairy animals. These findings are of particular interest in farm animals where health and production traits are important for animal welfare and for economic gains.
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Wang CH, Chung MH, Chan P, Tsai JC, Chen FC. Effects of endurance exercise training on risk components for metabolic syndrome, interleukin-6, and the exercise capacity of postmenopausal women. Geriatr Nurs 2014; 35:212-8. [PMID: 24679550 DOI: 10.1016/j.gerinurse.2014.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 01/28/2014] [Accepted: 02/03/2014] [Indexed: 12/21/2022]
Abstract
We conducted this study to investigate how an exercise program affects the risk components of metabolic syndrome (MS), serum interleukin (IL)-6 levels, and exercise capacity in postmenopausal women. A randomized clinical trial design was used. Women in an exercise group participated in a treadmill-exercise program for 12 weeks, whereas women in a control group maintained their customary lifestyle. Data on variables were collected at baseline and after 12 weeks of the study, which was completed by 46 women (mean age, 56.0 ± 7.0 y). Our results indicate endurance exercise exerted significant beneficial effects on waist circumference, serum high-density lipoprotein cholesterol (HDL-C) and IL-6 levels, and exercise capacity (all P < 0.05). The beneficial effects on IL-6 and exercise capacity were correlated with improvements in HDL-C levels (r = -0.33, P = 0.03 and r = 0.31, P = 0.04, respectively). Our results suggest that health-care providers can incorporate an exercise program in treatments to improve the health of postmenopausal women.
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Affiliation(s)
- Chia-Hui Wang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C; Department of Nursing, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, R.O.C
| | - Min-Huey Chung
- Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Paul Chan
- College of Nursing, Taipei Medical University, Taipei, Taiwan, R.O.C; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Jen-Chen Tsai
- School of Nursing, National Yang-Ming University, No.155, Sec. 2, Linong Street, Taipei 112, Taiwan, R.O.C.
| | - Feng-Chia Chen
- Department of Laboratory Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, R.O.C
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20
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Menezes-Garcia Z, Oliveira MC, Lima RL, Soriani FM, Cisalpino D, Botion LM, Teixeira MM, Souza DG, Ferreira AVM. Lack of platelet-activating factor receptor protects mice against diet-induced adipose inflammation and insulin-resistance despite fat pad expansion. Obesity (Silver Spring) 2014; 22:663-72. [PMID: 24339378 DOI: 10.1002/oby.20142] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Accepted: 10/22/2012] [Indexed: 01/14/2023]
Abstract
OBJECTIVE The role of platelet-activating factor (PAF) on diet-induced inflammatory and metabolic dysfunction is unknown. The effects of diet-induced metabolic and inflammatory dysfunction in mice with deletion of the PAF receptor (PAFR(-/-) ) were evaluated in this study. METHODS Wild-type and PAFR(-/-) mice were fed chow (WT-C and PAFR(-/-) -C) or high-refined carbohydrate-containing diet (WT-HC and PAFR(-/-) -HC). PAFR(-/-) - RESULTS: HC mice gained more weight and adiposity than PAFR(-/-) -C and WT-HC mice. Lipogenesis increased and hormone-sensitive lipase expression decreased in PAFR(-/-) -HC compared to WT-HC mice. WT-HC mice had impaired glucose tolerance and insulin sensitivity compared to WT-C mice. In contrast, glucose tolerance and insulin sensitivity in PAFR(-/-) -HC mice were similar to that of lean littermates. PAFR(-/-) -HC mice expressed significantly more peroxisome proliferator-activator receptor gamma (PPARγ) than PAFR(-/-) -C and WT-C mice. Resistin increased in WT-HC mice compared to WT-C mice. However, the levels of resistin were 35% lower in PAFR(-/-) -HC mice than WT-HC mice. PAFR(-/-) presented with less HC diet-induced adipose tissue inflammation than WT mice. Adipocytes isolated from PAFR(-/-) mice incubated in media containing normal or high levels of glucose secreted less interleukin-6 and tumor necrosis factor alpha and presented lower rate of lipolysis than WT mice. CONCLUSION PAFR deficiency resulted in less inflammation in adipose tissue and improvement in glucose homeostasis when fed the HC diet. The higher adiposity observed in PAFR(-/-) mice fed HC diet could be owing to the maintenance of insulin sensitivity, decreased adipocyte lipolysis rate, high lipogenesis and PPARγ expression, and lower inflammatory milieu in adipose tissue.
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Affiliation(s)
- Zélia Menezes-Garcia
- Department of Microbiology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Department of Biochemistry and Immunology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 2014; 26:54-74. [PMID: 24552665 DOI: 10.1016/j.smim.2014.01.001] [Citation(s) in RCA: 527] [Impact Index Per Article: 47.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 01/06/2014] [Indexed: 11/17/2022]
Abstract
Inflammatory responses play pivotal roles in cancer development, including tumor initiation, promotion, progression, and metastasis. Cytokines are now recognized as important mediators linking inflammation and cancer, and are therefore potential therapeutic and preventive targets as well as prognostic factors. The interleukin (IL)-6 family of cytokines, especially IL-6 and IL-11, is highly up-regulated in many cancers and considered as one of the most important cytokine families during tumorigenesis and metastasis. This review discusses molecular mechanisms linking the IL-6 cytokine family to solid malignancies and their treatment.
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Affiliation(s)
- Koji Taniguchi
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; UC San Diego Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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22
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Gonzales GF, Gasco M, Lozada I. Role of maca (Lepidium meyenii) consumption on serum interleukin-6 levels and health status in populations living in the Peruvian Central Andes over 4000 m of altitude. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2013; 68:347-51. [PMID: 23934543 PMCID: PMC3856628 DOI: 10.1007/s11130-013-0378-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Lepidium meyenii (Maca) is a plant that grows at over 4,000 m above sea level in the central Peruvian Andes. The hypocotyls of this plant are traditionally consumed for their nutritional and medicinal properties. The aim of this study was to determine the health status based on a health related quality of life (HRQL) questionnaire (SF-20) and serum levels of interleukin 6 (IL-6) in subjects that are maca consumers. For this, a cross-sectional study was designed to be performed in 50 subjects from Junin (4,100 m): 27 subjects were maca consumers and 23 were non-consumers. The SF-20 survey is used to obtain a summary measure of health status. The stand up from a chair and sit down (SUCSD) test (to assess lower-extremity function), hemoglobin measurement, blood pressure, sexual hormone levels, serum IL-6 levels and the score of chronic mountain sickness (CMS) were evaluated. Testosterone/estradiol ratio (P <0.05), IL-6 (P < 0.05) and CMS score were lower, whereas the health status score was higher, in maca consumers when compared to non-consumers (P < 0.01). A greater proportion of maca consumers successfully completed the SUCSD test compared to non-consumers (P < 0.01), showing a significant association with lower values of serum IL-6 (P < 0.05). In conclusion, consumption of maca was associated with low serum IL-6 levels and in turn with better health status scores in the SF-20 survey and low chronic mountain sickness scores.
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Affiliation(s)
- Gustavo F. Gonzales
- Laboratory of Endocrinology and Reproduction, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia
- Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Manuel Gasco
- Laboratory of Endocrinology and Reproduction, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia
- Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Ivan Lozada
- Laboratory of Immunology, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia
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23
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Coimbra S, Catarino C, Santos-Silva A. The role of adipocytes in the modulation of iron metabolism in obesity. Obes Rev 2013; 14:771-9. [PMID: 23841713 DOI: 10.1111/obr.12057] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 04/29/2013] [Accepted: 05/24/2013] [Indexed: 02/06/2023]
Abstract
A tight relationship between iron deficiency and obesity is known to exist. The chronic low-grade inflammation that characterizes obesity enhances hepcidin production, the principal regulator of iron availability. Adipose tissue is known to secret interleukin-6 and leptin that triggers hepcidin production. It was found that adipose tissue also expresses hepcidin and hemojuvelin, a regulator of hepcidin production. These recent findings suggest that adipose tissue may have an important role in erythropoiesis particularly on obesity that is still poorly clarified. This paper discusses these findings and how they can modulate erythropoiesis.
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Affiliation(s)
- S Coimbra
- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra-PRD, Portugal
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24
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High-fat feeding rapidly induces obesity and lipid derangements in C57BL/6N mice. Mamm Genome 2013; 24:240-51. [PMID: 23712496 PMCID: PMC3685703 DOI: 10.1007/s00335-013-9456-0] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Accepted: 04/11/2013] [Indexed: 02/07/2023]
Abstract
C57BL/6N (B6N) is becoming the standard background for genetic manipulation of the mouse genome. The B6N, whose genome is very closely related to the reference C57BL/6J genome, is versatile in a wide range of phenotyping and experimental settings and large repositories of B6N ES cells have been developed. Here, we present a series of studies showing the baseline characteristics of B6N fed a high-fat diet (HFD) for up to 12 weeks. We show that HFD-fed B6N mice show increased weight gain, fat mass, and hypercholesterolemia compared to control diet-fed mice. In addition, HFD-fed B6N mice display a rapid onset of lipid accumulation in the liver with both macro- and microvacuolation, which became more severe with increasing duration of HFD. Our results suggest that the B6N mouse strain is a versatile background for studying diet-induced metabolic syndrome and may also represent a model for early nonalcoholic fatty liver disease.
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25
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Mandard S, Patsouris D. Nuclear control of the inflammatory response in mammals by peroxisome proliferator-activated receptors. PPAR Res 2013; 2013:613864. [PMID: 23577023 PMCID: PMC3614066 DOI: 10.1155/2013/613864] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 01/14/2013] [Accepted: 01/29/2013] [Indexed: 12/30/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPAR γ ability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPAR α and PPAR β / δ against the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig). In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits.
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Affiliation(s)
- Stéphane Mandard
- Centre de Recherche INSERM-UMR866 “Lipides, Nutrition, Cancer” Faculté de Médecine, Université de Bourgogne 7, Boulevard Jeanne d'Arc, 21079 Dijon Cedex, France
| | - David Patsouris
- Laboratoire CarMeN, UMR INSERM U1060/INRA 1235, Université Lyon 1, Faculté de Médecine Lyon Sud, 165 Chemin du Grand Revoyet, 69921 Oullins, France
- Department of Chemical Physiology, The Scripps Research Institute, MB-24, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
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26
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Pang J, Rhodes DH, Pini M, Akasheh RT, Castellanos KJ, Cabay RJ, Cooper D, Perretti M, Fantuzzi G. Increased adiposity, dysregulated glucose metabolism and systemic inflammation in Galectin-3 KO mice. PLoS One 2013; 8:e57915. [PMID: 23451284 PMCID: PMC3579848 DOI: 10.1371/journal.pone.0057915] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 01/27/2013] [Indexed: 12/14/2022] Open
Abstract
Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6Chigh monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.
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Affiliation(s)
- Jingbo Pang
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Davina H. Rhodes
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Rand T. Akasheh
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Karla J. Castellanos
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Robert J. Cabay
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Dianne Cooper
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Mauro Perretti
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Giamila Fantuzzi
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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27
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Adipocytes derived fibrinolytic components in peritoneum — a pilot study. Open Med (Wars) 2012. [DOI: 10.2478/s11536-012-0042-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractThe proteins of the fibrinolytic system — urokinase plasminogen activator(uPA), tissue plasminogen activator (tPA)and plasminogen activator inhibitor type IPAI-I) — play important roles in fibrotization in various organs and including peritoneum. To study the cellular localization of PAI-1, tPA and uPA within the adipose tissue of the peritoneal membrane in patients at the onset of peritoneal dialysis(PD) we determined the initial expression of these proteins in relationship to multiple clinical variables. Methods: routinely performed parietal peritoneal biopsies in 12 patients undergoing peritoneal catheter implantation were examined. We used formalinfixed, paraffin-embedded specimens for immunohistochemical localization of these proteins along with the stereological pointcounting method for quantification of their expression within the peritoneal adipose tissue. Results: strong positive mutual correlation between the expression of PAI-1 and both uPA (SpearmanR=0.66) and tPA (R=0.59) as well as between the expression of uPA and tPA (R=0.77) was found without any relatioship to BMI, age, peritoneal transport characteristic or diabetes status. Conclusion: Adipose tissue within the peritoneum is capable of producing fibrinolysis regulators (independently on clinical parameters) thus possibly affecting the fibrotization and function of peritoneum as dialysis membrane. The effect of dialysis solution dosing, composition and other dialysis related factors should be clarified in future studies.
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28
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Pini M, Castellanos KJ, Rhodes DH, Fantuzzi G. Obesity and IL-6 interact in modulating the response to endotoxemia in mice. Cytokine 2012; 61:71-7. [PMID: 23010503 DOI: 10.1016/j.cyto.2012.08.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 08/27/2012] [Indexed: 01/07/2023]
Abstract
Obesity is associated with elevated levels of IL-6. High IL-6 is prognostic of mortality in sepsis, while controversial data link obesity to sepsis outcome. We used Lean and diet-induced obese (DIO) WT and IL-6 KO mice to investigate the interaction between obesity and IL-6 in endotoxemia. Circulating levels of IL-6 were significantly higher in WT DIO versus WT Lean mice receiving LPS (2.5 μg/mouse, ip). Obesity lead to greater weight loss in response to LPS, with IL-6 deficiency being partially protective. Plasma TNFα, IFNγ, Galectin-3 and leptin were significantly elevated in response to LPS and were each differentially affected by obesity and/or IL-6 deficiency. Plasma Galectin-1 and adiponectin were significantly suppressed by LPS, with obesity and IL-6 deficiency modulating the response. However, LPS comparably increased IL-10 levels in each group. Leukopenia with relative neutrophilia and thrombocytopenia developed in each group after injection of LPS, with obesity and genotype affecting the kinetics, but not the magnitude, of the response. Hepatic induction of the acute-phase protein SAA by LPS was not affected by obesity or IL-6 deficiency, although baseline levels were highest in WT DIO mice. Injection of LPS significantly increased hepatic mRNA expression of PAI-1 in Lean WT and Lean KO mice, while it suppressed the high baseline levels observed in the liver of DIO WT and DIO KO mice. Thus, both IL-6 and obesity modulate the response to endotoxemia, suggesting a complex interaction that needs to be considered when evaluating the effect of obesity on the outcome of septic patients.
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Affiliation(s)
- Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, United States
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29
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Pini M, Rhodes DH, Castellanos KJ, Cabay RJ, Grady EF, Fantuzzi G. Rosiglitazone improves survival and hastens recovery from pancreatic inflammation in obese mice. PLoS One 2012; 7:e40944. [PMID: 22815875 PMCID: PMC3397967 DOI: 10.1371/journal.pone.0040944] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Accepted: 06/15/2012] [Indexed: 02/06/2023] Open
Abstract
Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice.
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Affiliation(s)
- Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Davina H. Rhodes
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Karla J. Castellanos
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Robert J. Cabay
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Eileen F. Grady
- Department of Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Giamila Fantuzzi
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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30
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Pini M, Rhodes DH, Castellanos KJ, Hall AR, Cabay RJ, Chennuri R, Grady EF, Fantuzzi G. Role of IL-6 in the resolution of pancreatitis in obese mice. J Leukoc Biol 2012; 91:957-66. [PMID: 22427681 DOI: 10.1189/jlb.1211627] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Obesity increases severity of acute pancreatitis and risk of pancreatic cancer. Pancreatitis and obesity are associated with elevated IL-6, a cytokine involved in inflammation and tumorigenesis. We studied the role of IL-6 in the response of lean and obese mice to pancreatitis induced by IL-12 + IL-18. Lean and diet-induced obese (DIO) WT and IL-6 KO mice and ob/ob mice pretreated with anti-IL-6 antibodies were evaluated at Days 1, 7, and 15 after induction of pancreatitis. Prolonged elevation of IL-6 in serum and visceral adipose tissue was observed in DIO versus lean WT mice, whereas circulating sIL-6R declined in DIO but not lean mice with pancreatitis. The severe inflammation and lethality of DIO mice were also observed in IL-6 KO mice. However, the delayed resolution of neutrophil infiltration; sustained production of CXCL1, CXCL2, and CCL2; prolonged activation of STAT-3; and induction of MMP-7 in the pancreas, as well as heightened induction of serum amylase A of DIO mice, were blunted significantly in DIO IL-6 KO mice. In DIO mice, production of OPN and TIMP-1 was increased for a prolonged period, and this was mediated by IL-6 in the liver but not the pancreas. Results obtained in IL-6 KO mice were confirmed in ob/ob mice pretreated with anti-IL-6 antibodies. In conclusion, IL-6 does not contribute to the increased severity of pancreatitis of obese mice but participates in delayed recovery from acute inflammation and may favor development of a protumorigenic environment through prolonged activation of STAT-3, induction of MMP-7, and sustained production of chemokines.
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Affiliation(s)
- Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
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