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Gaber M, Quentel A, Holmes J, Lepetit C, Triki H, Wilson A, Payne V, Tenvooren I, Dehours C, Peoples A, Duet ML, Katz AJ, Pécot T, Bougras-Cartron G, Cartron PF, Cook KL, Vidi PA. Obesity increases DNA damage in the breast epithelium. Breast Cancer Res 2025; 27:11. [PMID: 39838489 PMCID: PMC11753040 DOI: 10.1186/s13058-025-01961-7] [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: 06/27/2024] [Accepted: 01/10/2025] [Indexed: 01/23/2025] Open
Abstract
Obesity is a modifiable risk factor for breast cancer. Yet, how obesity contributes to cancer initiation is not fully understood. The goal of this study was to determine if the body mass index (BMI) and metabolic hallmarks of obesity are related to DNA damage in normal breast tissue. In a mouse model of diet-induced obesity, weight gain was associated with elevated levels of DNA double-strand breaks in the mammary gland. We also found a positive correlation between BMI and DNA breaks in the breast epithelium of premenopausal women (but not postmenopausal women). High BMI was associated with elevated systemic and tissue-level oxidative DNA damage across the lifespan, and we propose that the breast epithelium undergoing menstruous proliferation waves is particularly prone to the generation of DNA breaks from oxidative lesions. Ancestry was an important modulator of the obesity-DNA break connection. Compared to non-Hispanic Whites, women identifying as African Americans had higher levels of DNA breaks, as well as elevated leptin and IGF-1. In 3D cultures of breast acini, both leptin and IGF-1 caused an accumulation of DNA damage. The results highlight a connection between premalignant genomic alterations in the breast epithelium and metabolic health modulated by obesity and ancestry. They call for attention on biological determinants of breast cancer risk disparities.
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Affiliation(s)
- Mohamed Gaber
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Arnaud Quentel
- Institut de Cancérologie de l'Ouest, Angers, F-49055, France
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
| | - Julia Holmes
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | | | - Hana Triki
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
- Institut de Cancérologie de l'Ouest, Saint Herblain, F-44805, France
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Adam Wilson
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Valerie Payne
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Iliana Tenvooren
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Cloé Dehours
- Institut de Cancérologie de l'Ouest, Angers, F-49055, France
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
| | - Abigail Peoples
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Mary L Duet
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Adam J Katz
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Thierry Pécot
- Biosit, UAR 3480 CNRS - US 18 Inserm, Rennes University, Rennes, F-35042, France
| | - Gwenola Bougras-Cartron
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Pierre-François Cartron
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Katherine L Cook
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Pierre-Alexandre Vidi
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
- Institut de Cancérologie de l'Ouest, Angers, F-49055, France.
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France.
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Živković L, Pirković A, Topalović D, Borozan S, Bajić V, Srećković VD, Djelić N, Petrović H, Milić M, Spremo-Potparević B. Dihydroquercetin and biochaga reduce H2O2-induced DNA damage in peripheral blood mononuclear cells of obese women in vitro-a pilot study. Mutagenesis 2024; 39:318-326. [PMID: 39021207 DOI: 10.1093/mutage/geae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 07/17/2024] [Indexed: 07/20/2024] Open
Abstract
Systemic oxidative stress stemming from increased free radical production and reduced antioxidant capacity are common characteristics of obese individuals. Using hydrogen peroxide (H2O2) to induce DNA damage in vitro, in peripheral blood mononuclear cells (PBMCs) from obese subjects and controls, the DNA protective ability of dihidroqercetin (DHQ) and biochaga (B) alone or in combination, were evaluated. The effects of DHQ and B were estimated under two experimental conditions: pre-treatment, where cells were pre-incubated with the substances prior to H2O2 exposure; and post-treatment when cells were first exposed to H2 H2O2, and further treated with the compounds. DNA damage was evaluated using the comet assay. The results of pre- and post-treatment showed a significant decrease in DNA damage produced by H2O2 in the obese group. This decrease was not significant in control group probably due to a small number of subjects in this pilot study. More prominent attenuation was noted in the pre-treatment with DHQ (250 μg/ml). Analysis of antioxidant properties revealed that DHQ's remarkable reducing power, 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity, and potent∙OH scavenging properties may contribute to strong attenuation of H2O2-induced DNA damage. Also, B showed strong reducing power, DPPH, and ∙OH scavenging ability, while reducing power and DPPH scavenger effects were increased in the presence of DHQ. Conclusively, DHQ and B may reduce H2O2-induced DNA damage in PBMCs from obese subjects when challenged in vitro, and could be valuable tools in future research against oxidative damage-related conditions.
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Affiliation(s)
- Lada Živković
- Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, 11000, Belgrade, Serbia
| | - Andrea Pirković
- Department for Biology of Reproduction, University of Belgrade, Institute for Application of Nuclear Energy, 11000, Belgrade, Serbia
| | - Dijana Topalović
- Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, 11000, Belgrade, Serbia
| | - Sunčica Borozan
- Department of Chemistry, University of Belgrade, Faculty of Veterinary Medicine, 11000, Belgrade, Serbia
| | - Vladan Bajić
- Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Institute for Nuclear Research 'Vinča', 11000, Belgrade, Serbia
| | - Vesna Dimitrijević Srećković
- Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University of Belgrade, 11000, Belgrade, Serbia
| | - Ninoslav Djelić
- Department of Biology, University of Belgrade, Faculty of Veterinary Medicine, 11000, Belgrade, Serbia
| | - Hristina Petrović
- Faculty of Medicine, University of Belgrade, University Children's Hospital, 11000, Belgrade, Serbia
| | - Mirta Milić
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, 10000, Zagreb, Croatia
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Georgakopoulou VE, Lempesis IG, Trakas N, Sklapani P, He Y, Spandidos DA. Lung cancer and obesity: A contentious relationship (Review). Oncol Rep 2024; 52:158. [PMID: 39497438 PMCID: PMC11462394 DOI: 10.3892/or.2024.8817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 09/25/2024] [Indexed: 11/08/2024] Open
Abstract
The global obesity epidemic, attributed to sedentary lifestyles, unhealthy diets, genetics and environmental factors, has led to over 1.9 billion adults being classified as overweight and 650 million living with obesity. Despite advancements in early detection and treatment, lung cancer prognosis remains poor due to late diagnoses and limited therapies. The obesity paradox challenges conventional thinking by suggesting that individuals with obesity and certain diseases, including cancer, may have an improved prognosis compared with their counterparts of a normal weight. This observation has prompted investigations to understand protective mechanisms, including potentially favorable adipokine secretion and metabolic reserves that contribute to tolerating cancer treatments. However, understanding the association between obesity and lung cancer is complex. While smoking is the primary risk factor of lung cancer, obesity may independently impact lung cancer risk, particularly in non‑smokers. Adipose tissue dysfunction, including low‑grade chronic inflammation, and hormonal changes contribute to lung cancer development and progression. Obesity‑related factors may also influence treatment responses and survival outcomes in patients with lung cancer. The impact of obesity on treatment modalities such as chemotherapy, radiotherapy and surgery is still under investigation. Challenges in managing patients with obesity and cancer include increased surgical complexity, higher rates of postoperative complications and limited treatment options due to comorbidities. Targeted interventions aimed at reducing obesity prevalence and promoting healthy lifestyles are crucial for lung cancer prevention. The impact of obesity on lung cancer is multifaceted and requires further research to elucidate the underlying mechanisms and develop personalized interventions for prevention and treatment.
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Affiliation(s)
| | - Ioannis G. Lempesis
- Medical Chronobiology Program, Division of Sleep Medicine and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Nikolaos Trakas
- Department of Biochemistry, Sismanogleio Hospital, Athens 15126, Greece
| | - Pagona Sklapani
- Department of Biochemistry, Sismanogleio Hospital, Athens 15126, Greece
| | - Yutong He
- Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050010, P.R. China
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, Heraklion 71003, Greece
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Niu XT, Wang XY, Wang Y, Han K, Ru N, Xiang JY, Linghu EQ. Transcriptome analysis suggests broad jejunal alterations in Linghu's obesity-diarrhea syndrome: A pilot study. World J Gastroenterol 2024; 30:2777-2792. [PMID: 38899329 PMCID: PMC11185300 DOI: 10.3748/wjg.v30.i21.2777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND Obesity is associated with a significantly increased risk for chronic diarrhea, which has been proposed as Linghu's obesity-diarrhea syndrome (ODS); however, its molecular mechanisms are largely unknown. AIM To reveal the transcriptomic changes in the jejunum involved in ODS. METHODS In a cohort of 6 ODS patients (JOD group), 6 obese people without diarrhea (JO group), and 6 healthy controls (JC group), high-throughput sequencing and bioinformatics analyses were performed to identify jejunal mucosal mRNA expression alterations and dysfunctional biological processes. In another cohort of 16 ODS patients (SOD group), 16 obese people without diarrhea (SO group), and 16 healthy controls (SC group), serum diamine oxidase (DAO) and D-lactate (D-LA) concentrations were detected to assess changes in intestinal barrier function. RESULTS The gene expression profiles of jejunal mucosa in the JO and JC groups were similar, with only 1 differentially expressed gene (DEG). The gene expression profile of the JOD group was significantly changed, with 411 DEGs compared with the JO group and 211 DEGs compared with the JC group, 129 of which overlapped. The enrichment analysis of these DEGs showed that the biological processes such as digestion, absorption, and transport of nutrients (especially lipids) tended to be up-regulated in the JOD group, while the biological processes such as rRNA processing, mitochondrial translation, antimicrobial humoral response, DNA replication, and DNA repair tended to be down-regulated in the JOD group. Eight DEGs (CDT1, NHP2, EXOSC5, EPN3, NME1, REG3A, PLA2G2A, and PRSS2) may play a key regulatory role in the pathological process of ODS, and their expression levels were significantly decreased in ODS patients (P < 0.001). In the second cohort, compared with healthy controls, the levels of serum intestinal barrier function markers (DAO and D-LA) were significantly increased in all obese individuals (P < 0.01), but were higher in the SOD group than in the SO group (P < 0.001). CONCLUSION Compared with healthy controls and obese individuals without diarrhea, patients with Linghu's ODS had extensive transcriptomic changes in the jejunal mucosa, likely affecting intestinal barrier function and thus contributing to the obesity and chronic diarrhea phenotypes.
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Affiliation(s)
- Xiao-Tong Niu
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xiang-Yao Wang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yan Wang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Ke Han
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Nan Ru
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Jing-Yuan Xiang
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - En-Qiang Linghu
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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Gholami M. FTO is a major genetic link between breast cancer, obesity, and diabetes. Breast Cancer Res Treat 2024; 204:159-169. [PMID: 38071263 DOI: 10.1007/s10549-023-07188-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 10/26/2023] [Indexed: 01/24/2024]
Abstract
PURPOSE Breast cancer (BC), obesity, and type 2 diabetes mellitus (T2DM) are three complex diseases and health problems that are prevalent worldwide. The aim of this study was to investigate the common genetic associations between these diseases by referring back to the previous genome-wide association studies (GWAS). METHODS To this end, significant GWAS variants and common variants associated with BC, obesity, or diabetes were identified from the GWAS catalog. To perform candidate variants, the 1000-Genomes Project was used to find variants with linkage disequilibrium. Common variants between each category were identified (common candidate haplotypic variants). Finally, these variants and their associated genes were examined for SNP function analysis, gene expression, gene-gene correlation, and pathway analysis. RESULTS The results identified 7 variants associated with both T2DM and BC, 8 variants associated with both obesity and BC, and 167 variants associating obesity with T2DM. 91 variants and 4 haplotypic blocks such as CTC were identified on the FTO gene associated with obesity, BC, and T2DM. The results of TCGA data showed that FTO in gene expression was correlated with 6 other genes in the DNA repair pathway in BC subjects. CONCLUSIONS This study suggests that the FTO gene is one of the major genes shared by BC, T2DM, and obesity based on two DNA repair and inflammatory mechanisms. These results may provide a new perspective on the important role of the FTO gene and repair mechanism in the relationship between BC, obesity, and T2DM for future studies.
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Affiliation(s)
- Morteza Gholami
- Metabolic Disorders Research Center, Endocrinology and Metabolism Research Institute, North Kargar Ave, Tehran, Iran.
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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6
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Jovanović M, Kovačević S, Brkljačić J, Djordjevic A. Oxidative Stress Linking Obesity and Cancer: Is Obesity a 'Radical Trigger' to Cancer? Int J Mol Sci 2023; 24:ijms24098452. [PMID: 37176160 PMCID: PMC10179114 DOI: 10.3390/ijms24098452] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/24/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity is on the rise worldwide, and consequently, obesity-related non-communicable diseases are as well. Nutritional overload induces metabolic adaptations in an attempt to restore the disturbed balance, and the byproducts of the mechanisms at hand include an increased generation of reactive species. Obesity-related oxidative stress causes damage to vulnerable systems and ultimately contributes to neoplastic transformation. Dysfunctional obese adipose tissue releases cytokines and induces changes in the cell microenvironment, promoting cell survival and progression of the transformed cancer cells. Other than the increased risk of cancer development, obese cancer patients experience higher mortality rates and reduced therapy efficiency as well. The fact that obesity is considered the second leading preventable cause of cancer prioritizes the research on the mechanisms connecting obesity to cancerogenesis and finding the solutions to break the link. Oxidative stress is integral at different stages of cancer development and advancement in obese patients. Hypocaloric, balanced nutrition, and structured physical activity are some tools for relieving this burden. However, the sensitivity of simultaneously treating cancer and obesity poses a challenge. Further research on the obesity-cancer liaison would offer new perspectives on prevention programs and treatment development.
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Affiliation(s)
- Mirna Jovanović
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Sanja Kovačević
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Jelena Brkljačić
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Ana Djordjevic
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
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Varun K, Zoltan K, Alba S, Manuel B, Elisabeth K, Dimitrios T, Jan B G, Maik B, Khurrum S, Berend I, Stephen H, Thomas F, Julia S, Peter N, Stefan K. Elevated markers of DNA damage and senescence are associated with the progression of albuminuria and restrictive lung disease in patients with type 2 diabetes. EBioMedicine 2023; 90:104516. [PMID: 36934657 PMCID: PMC10025008 DOI: 10.1016/j.ebiom.2023.104516] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 02/09/2023] [Accepted: 02/22/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND This study was conducted to investigate the cascade involving DNA damage, senescence, and senescence-associated secretory phenotype (SASP) in experimental diabetes and in a four-year follow-up study in patients with pre-diabetes and type 2 diabetes. METHODS Kidney, lung, and liver were studied in 4 months diabetic db/db mice and age-matched controls for the presence of DNA damage and fibrosis. DNA damage (comet-tail-length and ɤH2Ax-positivity in white blood cells), urinary p21-excretion, and plasma IL-6 and TGF-β1 were determined from 115 healthy participants, 34 patients with pre-diabetes and 221 with type 2 diabetes. Urinary albumin-creatinine-ratio, lung function, and transient elastography of the liver were performed in a prospective follow-up study over 4 years. FINDINGS db/db mice showed an increased nuclear ɤH2AX signal in all tissues as compared to the background control. Markers for DNA damage, senescence, and SASP were increased in patients with diabetes. The presence of nephropathy, restrictive lung disease (RLD), and increased liver stiffness was in a cross-sectional design associated with increased markers for DNA damage, senescence, and SASP. The progression of nephropathy over 4 years was predicted by increased DNA damage, senescence, and SASP, while the progression of RLD was associated with increased DNA damage and IL-6 only. The progression of liver stiffness was not associated with any of these parameters. HbA1c was not predictive for progression. INTERPRETATION In db/db mice, the cascade of DNA damage is associated with diabetes-related complications. In patients with diabetes, the progression of complications in the kidney and lung is predicted by markers reflecting DNA damage, and senescence-triggered organ fibrosis. FUNDING This work was supported by the German Research Foundation (DFG) in the CRC 1118 and CRC 1158, by the GRK DIAMICOM, by the German Center for Diabetes Research (DZD e.V.), and by the Ministry of Science, Research and the Arts, Baden-Württemberg (Kompetenznetzwerk Präventivmedizin).
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Affiliation(s)
- Kumar Varun
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; European Molecular Biology Laboratory, Advanced Light Microscopy Facility, Heidelberg, Germany
| | - Kender Zoltan
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Sulaj Alba
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Blume Manuel
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany
| | - Kliemank Elisabeth
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Tsilingiris Dimitrios
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Groener Jan B
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Medicover Neuroendokrinologie, Munich, Germany
| | - Brune Maik
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany
| | - Shahzad Khurrum
- Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital of Leipzig, Germany
| | - Isermann Berend
- Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital of Leipzig, Germany
| | - Herzig Stephen
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Helmholtz Diabetes Center, Institute for Diabetes and Cancer, Helmholtz Center Munich, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany
| | - Fleming Thomas
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Szendroedi Julia
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Nawroth Peter
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany
| | - Kopf Stefan
- Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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Dalberto D, Garcia ALH, De Souza MR, Picinini J, Soares S, De Souza GMS, Chytry P, Dias JF, Salvador M, Da Silva FR, Da Silva J. Dry tobacco leaves: an in vivo and in silico approach to the consequences of occupational exposure. Mutagenesis 2023; 38:120-130. [PMID: 36738258 DOI: 10.1093/mutage/gead003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Exposure of tobacco workers handling dried tobacco leaves has been linked to an increased risk of toxicity and respiratory illness due to the presence of nicotine and other chemicals. This study aimed to evaluate the DNA damage caused by the exposure of tobacco growers during the dry leaf classification process and the relation to cellular mechanisms. A total of 86 individuals participated in the study, divided into a group exposed to dry tobacco (n = 44) and a control group (n = 42). Genotoxicity was evaluated using the alkaline comet assay and lymphocyte micronucleus (MN) assay (CBMN-Cyt), and measurement of telomere length. The levels of oxidative and nitrosative stress were evaluated through the formation of thiobarbituric acid reactive species, and nitric oxide levels, respectively. The inorganic elements were measured in the samples using particle-induced X-ray emission method. The combination of variables was demonstrated through principal component analysis and the interactions were expanded through systems biology. Comet assay, MN, death cells, thiobarbituric acid reactive species, and nitrosative stress showed a significant increase for all exposed groups in relation to the control. Telomere length showed a significant decrease for exposed women and total exposed group in relation to men and control groups, respectively. Bromine (Br) and rubidium (Rb) in the exposed group presented higher levels than control groups. Correlations between nitrate and apoptosis; Br and MN and necrosis; and Rb and telomeres; besides age and DNA damage and death cells were observed. The systems biology analysis demonstrated that tobacco elements can increase the nuclear translocation of NFKB dimers inducing HDAC2 expression, which, associated with BRCA1 protein, can potentially repress transcription of genes that promote DNA repair. Dry tobacco workers exposed to dry leaves and their different agents showed DNA damage by different mechanisms, including redox imbalance.
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Affiliation(s)
- Daiana Dalberto
- Laboratory of Genetic Toxicology, PPGBioSaúde, Lutheran University of Brazil (ULBRA), Canoas, RS, Brazil
| | - Ana L H Garcia
- Laboratory of Genetic Toxicology, PPGBioSaúde, Lutheran University of Brazil (ULBRA), Canoas, RS, Brazil.,Laboratory of Genetic Toxicology, PPGSDH, La Salle University (UniLaSalle), Canoas, RS, Brazil
| | - Melissa R De Souza
- Laboratory of Genetic Toxicology, PPGBioSaúde, Lutheran University of Brazil (ULBRA), Canoas, RS, Brazil
| | - Juliana Picinini
- Laboratory of Genetic Toxicology, PPGBioSaúde, Lutheran University of Brazil (ULBRA), Canoas, RS, Brazil
| | - Solange Soares
- Laboratory of Genetic Toxicology, PPGBioSaúde, Lutheran University of Brazil (ULBRA), Canoas, RS, Brazil
| | - Guilherme M S De Souza
- Ion Implantation Laboratory, Institute of Physics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Paola Chytry
- Ion Implantation Laboratory, Institute of Physics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Johnny F Dias
- Ion Implantation Laboratory, Institute of Physics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Mirian Salvador
- Biotechnology Institute, University of Caxias do Sul, Caxias do Sul (UCS), RS, Brazil
| | - Fernanda R Da Silva
- Laboratory of Genetic Toxicology, PPGSDH, La Salle University (UniLaSalle), Canoas, RS, Brazil
| | - Juliana Da Silva
- Laboratory of Genetic Toxicology, PPGBioSaúde, Lutheran University of Brazil (ULBRA), Canoas, RS, Brazil.,Laboratory of Genetic Toxicology, PPGSDH, La Salle University (UniLaSalle), Canoas, RS, Brazil
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Sanhueza S, Simón L, Cifuentes M, Quest AFG. The Adipocyte-Macrophage Relationship in Cancer: A Potential Target for Antioxidant Therapy. Antioxidants (Basel) 2023; 12:126. [PMID: 36670988 PMCID: PMC9855200 DOI: 10.3390/antiox12010126] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 01/06/2023] Open
Abstract
Obesity has emerged as a major public health concern with a staggering 39% worldwide prevalence as of 2021. Given the magnitude of the problem and considering its association with chronic low-grade systemic inflammation, it does not come as a surprise that obesity is now considered one of the major risk factors for the development of several chronic diseases, such as diabetes, cardiovascular problems, and cancer. Adipose tissue dysfunction in obesity has taken center stage in understanding how changes in its components, particularly adipocytes and macrophages, participate in such processes. In this review, we will initially focus on how changes in adipose tissue upon excess fat accumulation generate endocrine signals that promote cancer development. Moreover, the tumor microenvironment or stroma, which is also critical in cancer development, contains macrophages and adipocytes, which, in reciprocal paracrine communication with cancer cells, generate relevant signals. We will discuss how paracrine signaling in the tumor microenvironment between cancer cells, macrophages, and adipocytes favors cancer development and progression. Finally, as reactive oxygen species participate in many of these signaling pathways, we will summarize the information available on how antioxidants can limit the effects of endocrine and paracrine signaling due to dysfunctional adipose tissue components in obesity.
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Affiliation(s)
- Sofía Sanhueza
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Laboratory of Obesity and Metabolism in Geriatrics and Adults (OMEGA), Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago 7830490, Chile
| | - Layla Simón
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Escuela de Nutrición y Dietética, Universidad Finis Terrae, Santiago 7501015, Chile
| | - Mariana Cifuentes
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Laboratory of Obesity and Metabolism in Geriatrics and Adults (OMEGA), Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago 7830490, Chile
| | - Andrew F. G. Quest
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
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10
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Ghanemi A, Yoshioka M, St-Amand J. DNA Damage as a Mechanistic Link between Air Pollution and Obesity? MEDICINES (BASEL, SWITZERLAND) 2022; 10:medicines10010004. [PMID: 36662488 PMCID: PMC9863819 DOI: 10.3390/medicines10010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/15/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022]
Abstract
It has been shown that the risk of developing obesity, a serious modern health problem, increases with air pollution. However, the molecular links are yet to be fully elucidated. Herein, we propose a hypothesis via which air pollution-induced DNA damage would be the mechanistic link between air pollution and the enhanced risk of obesity and overweight. Indeed, whereas air pollution leads to DNA damage, DNA damage results in inflammation, oxidative stress and metabolic impairments that could be behind energy balance changes contributing to obesity. Such thoughts, worth exploring, seems an important starting point to better understand the impact of air pollution on obesity development independently from the two main energy balance pillars that are diet and physical activity. This could possibly lead to new applications both for therapies as well as for policies and regulations.
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Affiliation(s)
- Abdelaziz Ghanemi
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada
- Functional Genomics Laboratory, Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada
| | - Mayumi Yoshioka
- Functional Genomics Laboratory, Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada
| | - Jonny St-Amand
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada
- Functional Genomics Laboratory, Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada
- Correspondence:
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11
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Marchi PH, Vendramini THA, Perini MP, Zafalon RVA, Amaral AR, Ochamotto VA, Da Silveira JC, Dagli MLZ, Brunetto MA. Obesity, inflammation, and cancer in dogs: Review and perspectives. Front Vet Sci 2022; 9:1004122. [PMID: 36262532 PMCID: PMC9573962 DOI: 10.3389/fvets.2022.1004122] [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: 07/26/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Obesity is the most common nutritional disease in dogs, and its prevalence has increased in recent decades. Several countries have demonstrated a prevalence of obesity in dogs similar to that observed in humans. Chronic low-grade inflammation is a prominent basis used to explain how obesity results in numerous negative health consequences. This is well known and understood, and recent studies have pointed to the association between obesity and predisposition to specific types of cancers and their complications. Such elucidations are important because, like obesity, the prevalence of cancer in dogs has increased in recent decades, establishing cancer as a significant cause of death for these animals. In the same way, intensive advances in technology in the field of human and veterinary medicine (which even proposes the use of animal models) have optimized existing therapeutic methods, led to the development of innovative treatments, and shortened the time to diagnosis of cancer. Despite the great challenges, this review aims to highlight the evidence obtained to date on the association between obesity, inflammation, and cancer in dogs, and the possible pathophysiological mechanisms that link obesity and carcinogenesis. The potential to control cancer in animals using existing knowledge is also presented.
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Affiliation(s)
- Pedro H. Marchi
- Pet Nutrology Research Center, Department of Animal Nutrition and Production of the School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Thiago H. A. Vendramini
- Pet Nutrology Research Center, Department of Animal Nutrition and Production of the School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Mariana P. Perini
- Pet Nutrology Research Center, Department of Animal Nutrition and Production of the School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Rafael V. A. Zafalon
- Pet Nutrology Research Center, Department of Animal Nutrition and Production of the School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Andressa R. Amaral
- Veterinary Nutrology Service, Veterinary Teaching Hospital of the School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Vanessa A. Ochamotto
- Pet Nutrology Research Center, Department of Animal Nutrition and Production of the School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Juliano C. Da Silveira
- Laboratory of Molecular, Morphophysiology and Development (LMMD), Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Maria L. Z. Dagli
- Laboratory of Experimental and Comparative Oncology, Department of Pathology, School of Veterinary Medicine and Animal Science of the University of São Paulo, São Paulo, Brazil
| | - Marcio A. Brunetto
- Pet Nutrology Research Center, Department of Animal Nutrition and Production of the School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil,Veterinary Nutrology Service, Veterinary Teaching Hospital of the School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil,*Correspondence: Marcio A. Brunetto
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12
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Ožvald I, Božičević D, Duh L, Vinković Vrček I, Domijan AM, Milić M. Changes in anthropometric, biochemical, oxidative, and DNA damage parameters after 3-weeks-567-kcal-hospital-controlled-VLCD in severely obese patients with BMI ≥ 35 kg m -2. Clin Nutr ESPEN 2022; 49:319-327. [PMID: 35623833 DOI: 10.1016/j.clnesp.2022.03.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND & AIMS Severe obesity and its comorbidities relate to increased genomic instability/cancer risk. Obesity in Croatia is rapidly increasing, and long diets are sometimes the reason for obese to quit health improvement programs. A shorter diet with more strict calorie reduction could also lead to weight reduction and health improvements, but data are scarce. We tested for the first time if a very low-calorie diet (VLCD) can improve anthropometric, biochemical and genomic stability parameters in severely obese with BMI ≥ 35 kg m-2. METHODS 22 participants were chosen among those regularly attending the hospital for obesity control, with no other previous treatment for bodyweight reduction. Under 24 h medical surveillance, patients received 3-weeks-567-kcal-hospital-controlled-VLCD composed of 50-60% complex carbohydrates, 20-25% proteins, and 25-30% fat, with the attention to food carbo-glycemic index, in 3 meals freshly prepared in hospital. We analyzed changes in body weight, BMI, basal metabolism rate, waist-hip ratio, visceral fat level, body fat mass, percent body fat, skeletal muscle mass, basal metabolism, energy intake, lipid profile, thyroid hormones, TSH, and genomic instability (alkaline and oxidative FPG comet assay) before and on the last VLCD day. RESULTS Diet caused BMI reduction (in average 3-4 BMI units' loss), excessive weight loss (between 10 and 35%), significant weight loss (average 9 kg, range 4.8-14.4 kg) and a significant decrease in glucose, insulin, urea, cholesterol, HDL-c, LDL-c, oxidative (FPG) and DNA damage (alkaline comet assay) levels. CONCLUSIONS The diet can lead to ≥10% excessive weight loss, significant health, and genomic stability improvement, and keep severely obese interest in maintaining healthy habits. The study was registered at ClinicalTrials.gov as NCT05007171 (10.08.2021).
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Affiliation(s)
- Ivan Ožvald
- Special Hospital for Extended Treatment of Duga Resa, 47250 Duga Resa, Croatia
| | - Dragan Božičević
- Special Hospital for Extended Treatment of Duga Resa, 47250 Duga Resa, Croatia
| | - Lidija Duh
- Special Hospital for Extended Treatment of Duga Resa, 47250 Duga Resa, Croatia
| | - Ivana Vinković Vrček
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health (IMROH), 10 001 Zagreb, Croatia
| | - Ana-Marija Domijan
- Department of Pharmaceutical Botany, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000 Zagreb, Croatia
| | - Mirta Milić
- Mutagenesis Unit, Institute for Medical Research and Occupational Health (IMROH), 10 001 Zagreb, Croatia.
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13
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Opattova A, Langie SAS, Milic M, Collins A, Brevik A, Coskun E, Dusinska M, Gaivão I, Kadioglu E, Laffon B, Marcos R, Pastor S, Slyskova J, Smolkova B, Szilágyi Z, Valdiglesias V, Vodicka P, Volkovova K, Bonassi S, Godschalk RWL. A pooled analysis of molecular epidemiological studies on modulation of DNA repair by host factors. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2022; 876-877:503447. [PMID: 35483778 DOI: 10.1016/j.mrgentox.2022.503447] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 12/06/2021] [Accepted: 01/10/2022] [Indexed: 02/09/2023]
Abstract
Levels of DNA damage represent the dynamics between damage formation and removal. Therefore, to better interpret human biomonitoring studies with DNA damage endpoints, an individual's ability to recognize and properly remove DNA damage should be characterized. Relatively few studies have included DNA repair as a biomarker and therefore, assembling and analyzing a pooled database of studies with data on base excision repair (BER) was one of the goals of hCOMET (EU-COST CA15132). A group of approximately 1911 individuals, was gathered from 8 laboratories which run population studies with the comet-based in vitro DNA repair assay. BER incision activity data were normalized and subsequently correlated with various host factors. BER was found to be significantly higher in women. Although it is generally accepted that age is inversely related to DNA repair, no overall effect of age was found, but sex differences were most pronounced in the oldest quartile (>61 years). No effect of smoking or occupational exposures was found. A body mass index (BMI) above 25 kg/m2 was related to higher levels of BER. However, when BMI exceeded 35 kg/m2, repair incision activity was significantly lower. Finally, higher BER incision activity was related to lower levels of DNA damage detected by the comet assay in combination with formamidopyrimidine DNA glycosylase (Fpg), which is in line with the fact that oxidatively damaged DNA is repaired by BER. These data indicate that BER plays a role in modulating the steady-state level of DNA damage that is detected in molecular epidemiological studies and should therefore be considered as a parallel endpoint in future studies.
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Affiliation(s)
- Alena Opattova
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, 14200, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, 12800, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, 306 05, Czech Republic
| | - Sabine A S Langie
- Department of Pharmacology & Toxicology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, the Netherlands
| | - Mirta Milic
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | | | - Asgeir Brevik
- Oslo Metropolitan University, Faculty of Health Sciences, PO Box 4, St. Olavs plass, 0130, Oslo, Norway
| | - Erdem Coskun
- Gazi University, Faculty of Pharmacy, Department of Toxicology, Etiler, Ankara, 06330, Turkey
| | - Maria Dusinska
- Health Effects Laboratory, Department of Environmental Chemistry, Norwegian Institute for Air Research (NILU), 2002, Kjeller, Norway
| | - Isabel Gaivão
- Genetics and Biotechnology Department and Veterinary and Animal Research Centre (CECAV), Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - Ela Kadioglu
- Gazi University, Faculty of Pharmacy, Department of Toxicology, Etiler, Ankara, 06330, Turkey
| | - Blanca Laffon
- Instituto de Investigación Biomédica de A Coruña (INIBIC), AE CICA-INIBIC. Oza, 15071, A Coruña, Spain; Universidade da Coruña, Grupo DICOMOSA, Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Psicología, Facultad de Ciencias de la Educación, Campus Elviña s/n, 15071, A Coruña, Spain
| | - Ricard Marcos
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain
| | - Susana Pastor
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain
| | - Jana Slyskova
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, 14200, Czech Republic
| | - Bozena Smolkova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, 84505, Bratislava, Slovakia
| | - Zsófia Szilágyi
- Department of Non-ionizing Radiation, National Public Health Center, H-1221, Budapest, Hungary
| | - Vanessa Valdiglesias
- Instituto de Investigación Biomédica de A Coruña (INIBIC), AE CICA-INIBIC. Oza, 15071, A Coruña, Spain; Universidade da Coruña, Grupo DICOMOSA, Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Biología, Facultad de Ciencias, Campus A Zapateira s/n, 15071, A Coruña, Spain
| | - Pavel Vodicka
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, 14200, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, 12800, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, 306 05, Czech Republic
| | - Katarina Volkovova
- Department of Biology, Faculty of Medicine, Slovak Medical University, 833 03, Bratislava, Slovakia
| | - Stefano Bonassi
- Unit of Clinical and Molecular Epidemiology, IRCCS, San Raffaele Pisana, Rome, Italy; Department of Human Sciences and Quality of Life Promotion, San Raffaele University, Rome, Italy
| | - Roger W L Godschalk
- Department of Pharmacology & Toxicology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, the Netherlands.
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14
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Ožvald I, Božičević D, Duh L, Vinković Vrček I, Pavičić I, Domijan AM, Milić M. Effects of a 3-Week Hospital-Controlled Very-Low-Calorie Diet in Severely Obese Patients. Nutrients 2021; 13:4468. [PMID: 34960018 PMCID: PMC8703721 DOI: 10.3390/nu13124468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/10/2021] [Accepted: 12/11/2021] [Indexed: 11/28/2022] Open
Abstract
Although a very-low-calorie diet (VLCD) is considered safe and has demonstrated benefits among other types of diets, data are scarce concerning its effects on improving health and weight loss in severely obese patients. As part of the personalized weight loss program developed at the Duga Resa Special Hospital for Extended Treatment, Croatia, we evaluated anthropometric, biochemical, and permanent DNA damage parameters (assessed with the cytochalasin B-blocked micronucleus cytome assay-CBMN) in severely obese patients (BMI ≥ 35 kg m-2) after 3-weeks on a 567 kcal, hospital-controlled VLCD. This is the first study on the permanent genomic (in)stability in such VLCD patients. VLCDs caused significant decreases in weight (loss), parameters of the lipid profile, urea, insulin resistance, and reduced glutathione (GSH). Genomic instability parameters were lowered by half, reaching reference values usually found in the healthy population. A correlation was found between GSH decrease and reduced DNA damage. VLCDs revealed susceptible individuals with remaining higher DNA damage for further monitoring. In a highly heterogeneous group (class II and III in obesity, differences in weight, BMI, and other categories) consisting of 26 obese patients, the approach demonstrated its usefulness and benefits in health improvement, enabling an individual approach to further monitoring, diagnosis, treatment, and risk assessment based on changing anthropometric/biochemical VLCD parameters, and CBMN results.
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Affiliation(s)
- Ivan Ožvald
- Duga Resa Special Hospital for Extended Treatment, 47250 Duga Resa, Croatia; (I.O.); (D.B.); (L.D.)
| | - Dragan Božičević
- Duga Resa Special Hospital for Extended Treatment, 47250 Duga Resa, Croatia; (I.O.); (D.B.); (L.D.)
| | - Lidija Duh
- Duga Resa Special Hospital for Extended Treatment, 47250 Duga Resa, Croatia; (I.O.); (D.B.); (L.D.)
| | - Ivana Vinković Vrček
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health (IMROH), Ksaverska Cesta 2, 10001 Zagreb, Croatia;
| | - Ivan Pavičić
- Radiation Dosimetry and Radiobiology Unit, Institute for Medical Research and Occupational Health (IMROH), Ksaverska Cesta 2, 10001 Zagreb, Croatia;
| | - Ana-Marija Domijan
- Department of Pharmaceutical Botany, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia;
| | - Mirta Milić
- Mutagenesis Unit, Institute for Medical Research and Occupational Health (IMROH), Ksaverska Cesta 2, 10001 Zagreb, Croatia
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15
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Obesity, oxidative DNA damage and vitamin D as predictors of genomic instability in children and adolescents. Int J Obes (Lond) 2021; 45:2095-2107. [PMID: 34158611 PMCID: PMC8380542 DOI: 10.1038/s41366-021-00879-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 05/18/2021] [Accepted: 05/27/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND/OBJECTIVES Epidemiological evidence indicates obesity in childhood and adolescence to be an independent risk factor for cancer and premature mortality in adulthood. Pathological implications from excess adiposity may begin early in life. Obesity is concurrent with a state of chronic inflammation, a well-known aetiological factor for DNA damage. In addition, obesity has been associated with micro-nutritional deficiencies. Vitamin D has attracted attention for its anti-inflammatory properties and role in genomic integrity and stability. The aim of this study was to determine a novel approach for predicting genomic instability via the combined assessment of adiposity, DNA damage, systemic inflammation, and vitamin D status. SUBJECTS/METHODS We carried out a cross-sectional study with 132 participants, aged 10-18, recruited from schools and paediatric obesity clinics in London. Anthropometric assessments included BMI Z-score, waist and hip circumference, and body fat percentage via bioelectrical impedance. Inflammation and vitamin D levels in saliva were assessed by enzyme-linked immunosorbent assay. Oxidative DNA damage was determined via quantification of 8-hydroxy-2'-deoxyguanosine in urine. Exfoliated cells from the oral cavity were scored for genomic instability via the buccal cytome assay. RESULTS As expected, comparisons between participants with obesity and normal range BMI showed significant differences in anthropometric measures (p < 0.001). Significant differences were also observed in some measures of genomic instability (p < 0.001). When examining relationships between variables for all participants, markers of adiposity positively correlated with acquired oxidative DNA damage (p < 0.01) and genomic instability (p < 0.001), and negatively correlated with vitamin D (p < 0.01). Multiple regression analyses identified obesity (p < 0.001), vitamin D (p < 0.001), and oxidative DNA damage (p < 0.05) as the three significant predictors of genomic instability. CONCLUSIONS Obesity, oxidative DNA damage, and vitamin D deficiency are significant predictors of genomic instability. Non-invasive biomonitoring and predictive modelling of genomic instability in young patients with obesity may contribute to the prioritisation and severity of clinical intervention measures.
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16
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Franzke B, Schwingshackl L, Wagner KH. Chromosomal damage measured by the cytokinesis block micronucleus cytome assay in diabetes and obesity - A systematic review and meta-analysis. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2020; 786:108343. [DOI: 10.1016/j.mrrev.2020.108343] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/18/2020] [Accepted: 10/23/2020] [Indexed: 12/11/2022]
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17
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Bari A, Khan ZA, Shahzad SA, Raza Naqvi SA, Khan SA, Amjad H, Iqbal A, Yar M. Design and syntheses of 7-nitro-2-aryl-4 H-benzo[ d][1,3]oxazin-4-ones as potent anticancer and antioxidant agents. J Mol Struct 2020; 1214:128252. [PMID: 32292211 PMCID: PMC7153534 DOI: 10.1016/j.molstruc.2020.128252] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/10/2020] [Accepted: 04/11/2020] [Indexed: 12/19/2022]
Abstract
A group of new nitro substituted benzoxazinones (3a-k) were synthesized from easily available 4-nitroanthranilic acid. All the synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. Anti-proliferative and pro-apoptotic potential of all the synthesized compounds (3a-k) was evaluated by MTT and Hoechst 33258 staining assay respectively whereas their antioxidant properties were determined via DPPH free radical scavenging assay. The most active compounds (3a, 3c and 3k) showed significant cytotoxic potential against HeLa cells with an inhibition of cell viability that ranged between 28.54 and 44.67% (P < 0.001). Albeit statistically different, the anti-proliferative effect of 3c was in close match with that of the reference drug doxorubicin. Likewise, the test compounds showed profound pro-apoptotic potential with an apoptotic index that ranged between 52.86 and 75.61%. Besides, the docking studies revealed a higher efficiency for compounds (3a and 3h) owing to their better affinity and inhibition constant (Ki = 4.397 and 3.713 nmol) respectively. The antioxidant potential of synthesized benzoxazinones (3a-k) was in close agreement with the experimental anticancer results with a percent inhibition from 34.45 to 85.93% as compared to standard (90.56%).
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Affiliation(s)
- Ayesha Bari
- Department of Chemistry, Government College University, Faisalabad, 38000, Pakistan
| | - Zulfiqar Ali Khan
- Department of Chemistry, Government College University, Faisalabad, 38000, Pakistan
- Corresponding author. Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.
| | - Sohail Anjum Shahzad
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan
- Corresponding author. Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
| | - Syed Ali Raza Naqvi
- Department of Chemistry, Government College University, Faisalabad, 38000, Pakistan
| | - Shakeel Ahmad Khan
- Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, China
| | - Hira Amjad
- Department of Chemistry, Government College University, Lahore, 54000, Pakistan
| | - Ahsan Iqbal
- Department of Chemistry, Government College University, Faisalabad, 38000, Pakistan
| | - Muhammad Yar
- Interdisciplinary Research Center in Biomedical Materials, COMSATS University Islamabad, Lahore Campus, Lahore, 54000, Pakistan
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18
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Chung KM, Singh J, Lawres L, Dorans KJ, Garcia C, Burkhardt DB, Robbins R, Bhutkar A, Cardone R, Zhao X, Babic A, Vayrynen SA, Dias Costa A, Nowak JA, Chang DT, Dunne RF, Hezel AF, Koong AC, Wilhelm JJ, Bellin MD, Nylander V, Gloyn AL, McCarthy MI, Kibbey RG, Krishnaswamy S, Wolpin BM, Jacks T, Fuchs CS, Muzumdar MD. Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma. Cell 2020; 181:832-847.e18. [PMID: 32304665 PMCID: PMC7266008 DOI: 10.1016/j.cell.2020.03.062] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/13/2020] [Accepted: 03/27/2020] [Indexed: 12/30/2022]
Abstract
Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.
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Affiliation(s)
| | - Jaffarguriqbal Singh
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA
| | - Lauren Lawres
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA
| | | | - Cathy Garcia
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA
| | - Daniel B Burkhardt
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Rebecca Robbins
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
| | - Arjun Bhutkar
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
| | - Rebecca Cardone
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Xiaojian Zhao
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Ana Babic
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA
| | - Sara A Vayrynen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA
| | - Andressa Dias Costa
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA
| | - Jonathan A Nowak
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel T Chang
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA 94305, USA
| | - Richard F Dunne
- Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14627, USA
| | - Aram F Hezel
- Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14627, USA
| | - Albert C Koong
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Joshua J Wilhelm
- Schulze Diabetes Institute and Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN 55454, USA
| | - Melena D Bellin
- Schulze Diabetes Institute and Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN 55454, USA; Department of Pediatrics, University of Minnesota Medical Center, Minneapolis, MN 55454, USA
| | - Vibe Nylander
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Anna L Gloyn
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford OX3 7LE, UK
| | - Mark I McCarthy
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford OX3 7LE, UK
| | - Richard G Kibbey
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Smita Krishnaswamy
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02114, USA
| | - Tyler Jacks
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Charles S Fuchs
- Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT 06511, USA
| | - Mandar Deepak Muzumdar
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT 06511, USA.
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19
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Baderna D, Gadaleta D, Lostaglio E, Selvestrel G, Raitano G, Golbamaki A, Lombardo A, Benfenati E. New in silico models to predict in vitro micronucleus induction as marker of genotoxicity. JOURNAL OF HAZARDOUS MATERIALS 2020; 385:121638. [PMID: 31757721 DOI: 10.1016/j.jhazmat.2019.121638] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 11/03/2019] [Accepted: 11/07/2019] [Indexed: 06/10/2023]
Abstract
The evaluation of genotoxicity is a fundamental part of the safety assessment of chemicals due to the relevance of the potential health effects of genotoxicants. Among the testing methods available, the in vitro micronucleus assay with mammalian cells is one of the most used and required by regulations targeting several industrial sectors such as the cosmetic industry and food-related sectors. As an alternative to the testing methods, in recent years, lots in silico methods were developed to predict the genotoxicity of chemicals, including models for the Ames mutagenicity test, the in vitro chromosomal aberrations and the in vivo micronucleus assay. We developed several in silico models for the prediction of genotoxicity as reflected by the in vitro micronucleus assay. The resulting models include both statistical and knowledge-based models. The most promising model is the one based on fragments extracted with the SARpy platform. More than 100 structural alerts were extracted, including also fragments associated with the non-genotoxic activity. The model is characterized by high accuracy and the lowest false negative rate, making this tool suitable for chemical screening according to the regulators' needs. The SARpy model will be implemented on the VEGA platform (https://www.vegahub.eu) and will be freely available.
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Affiliation(s)
- Diego Baderna
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
| | - Domenico Gadaleta
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Eleonora Lostaglio
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Gianluca Selvestrel
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Giuseppa Raitano
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Azadi Golbamaki
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Anna Lombardo
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Emilio Benfenati
- Laboratory of Environmental Chemistry and Toxicology, Environmental Health Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
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20
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Iqbal A, Khan ZA, Shahzad SA, Ahmad Khan S, Raza Naqvi SA, Bari A, Amjad H, Umar MI. Synthesis, modeling studies and evaluation of E-stilbene hydrazides as potent anticancer agents. J Mol Struct 2019. [DOI: 10.1016/j.molstruc.2019.07.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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21
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Setayesh T, Mišík M, Langie SAS, Godschalk R, Waldherr M, Bauer T, Leitner S, Bichler C, Prager G, Krupitza G, Haslberger A, Knasmüller S. Impact of Weight Loss Strategies on Obesity-Induced DNA Damage. Mol Nutr Food Res 2019; 63:e1900045. [PMID: 31141317 PMCID: PMC6771950 DOI: 10.1002/mnfr.201900045] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 05/16/2019] [Indexed: 12/13/2022]
Abstract
SCOPE Obesity causes DNA damage, which is causally related to several disorders including cancer, infertility, and cognitive dysfunctions. The aim of this study is to investigate whether weight loss improves the integrity of the genetic material. METHODS AND RESULTS Overweight mice are fed ad libitum either with a Western diet (WD), with a 40% caloric restricted WD, or with a high carbohydrate low protein (HCLP) diet. Caloric restriction and also the HCLP diet lead to ca. 30% weight loss, which is paralleled by decreased DNA damage ("comet" formation) and oxidative damage of purines in inner organs, additionally the activity of nucleotide excision repair increased. The effects are more pronounced in animals that have received the HCLP chow. Results of biochemical analyses indicate that the reduction of DNA damage is associated with a decrease of pro-inflammatory cytokines and lower insulin levels. CONCLUSION The study indicates that weight loss may prevent obesity-associated adverse health effects due to reduction of overall DNA damage.
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Affiliation(s)
- Tahereh Setayesh
- Department of Internal Medicine IInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Miroslav Mišík
- Department of Internal Medicine IInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Sabine A. S. Langie
- VITO‐HealthMolBelgium
- Centre for Environmental SciencesHasselt UniversityHasseltBelgium
| | - Roger Godschalk
- Department of Pharmacology & ToxicologySchool for NutritionToxicology and Metabolism (NUTRIM)Maastricht UniversityMaastrichtThe Netherlands
| | - Monika Waldherr
- Department of Internal Medicine IInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Thomas Bauer
- Department of Internal Medicine IInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Sabine Leitner
- Department of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria
| | - Christoph Bichler
- Section of Endocrine SurgeryDivision of General SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
| | - Gerhard Prager
- Section of Endocrine SurgeryDivision of General SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
| | - Georg Krupitza
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | | | - Siegfried Knasmüller
- Department of Internal Medicine IInstitute of Cancer ResearchMedical University of ViennaViennaAustria
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22
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Kompella P, Vasquez KM. Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability. Mol Carcinog 2019; 58:1531-1550. [PMID: 31168912 PMCID: PMC6692207 DOI: 10.1002/mc.23048] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/08/2019] [Accepted: 05/10/2019] [Indexed: 12/16/2022]
Abstract
Obesity, defined as a state of positive energy balance with a body mass index exceeding 30 kg/m2 in adults and 95th percentile in children, is an increasing global concern. Approximately one-third of the world's population is overweight or obese, and in the United States alone, obesity affects one in six children. Meta-analysis studies suggest that obesity increases the likelihood of developing several types of cancer, and with poorer outcomes, especially in children. The contribution of obesity to cancer risk requires a better understanding of the association between obesity-induced metabolic changes and its impact on genomic instability, which is a major driving force of tumorigenesis. In this review, we discuss how molecular changes during adipose tissue dysregulation can result in oxidative stress and subsequent DNA damage. This represents one of the many critical steps connecting obesity and cancer since oxidative DNA lesions can result in cancer-associated genetic instability. In addition, the by-products of the oxidative degradation of lipids (e.g., malondialdehyde, 4-hydroxynonenal, and acrolein), and gut microbiota-mediated secondary bile acid metabolites (e.g., deoxycholic acid and lithocholic acid), can function as genotoxic agents and tumor promoters. We also discuss how obesity can impact DNA repair efficiency, potentially contributing to cancer initiation and progression. Finally, we outline obesity-related epigenetic changes and identify the gaps in knowledge to be addressed for the development of better therapeutic strategies for the prevention and treatment of obesity-related cancers.
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Affiliation(s)
- Pallavi Kompella
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA
| | - Karen M. Vasquez
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA
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23
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Rush EM, Gunderman RB. Radiology's Role in Public Health Education About Obesity. Acad Radiol 2019; 26:714-716. [PMID: 30777650 DOI: 10.1016/j.acra.2018.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 12/14/2018] [Indexed: 11/28/2022]
Affiliation(s)
- Evan M Rush
- Indiana University School of Medicine, 702 North Barnhill Drive, Room 1053, Indianapolis, Indiana 46202
| | - Richard B Gunderman
- Indiana University School of Medicine, 702 North Barnhill Drive, Room 1053, Indianapolis, Indiana 46202.
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24
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Azqueta A, Langie SAS, Boutet-Robinet E, Duthie S, Ladeira C, Møller P, Collins AR, Godschalk RWL. DNA repair as a human biomonitoring tool: Comet assay approaches. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:71-87. [PMID: 31416580 DOI: 10.1016/j.mrrev.2019.03.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 12/12/2022]
Abstract
The comet assay offers the opportunity to measure both DNA damage and repair. Various comet assay based methods are available to measure DNA repair activity, but some requirements should be met for their effective use in human biomonitoring studies. These conditions include i) robustness of the assay, ii) sources of inter- and intra-individual variability must be known, iii) DNA repair kinetics should be assessed to optimize sampling timing; and iv) DNA repair in accessible surrogate tissues should reflect repair activity in target tissues prone to carcinogenic effects. DNA repair phenotyping can be performed on frozen and fresh samples, and is a more direct measurement than genomic or transcriptomic approaches. There are mixed reports concerning the regulation of DNA repair by environmental and dietary factors. In general, exposure to genotoxic agents did not change base excision repair (BER) activity, whereas some studies reported that dietary interventions affected BER activity. On the other hand, in vitro and in vivo studies indicated that nucleotide excision repair (NER) can be altered by exposure to genotoxic agents, but studies on other life style related factors, such as diet, are rare. Thus, crucial questions concerning the factors regulating DNA repair and inter-individual variation remain unanswered. Intra-individual variation over a period of days to weeks seems limited, which is favourable for DNA repair phenotyping in biomonitoring studies. Despite this reported low intra-individual variation, timing of sampling remains an issue that needs further investigation. A correlation was reported between the repair activity in easily accessible peripheral blood mononuclear cells (PBMCs) and internal organs for both NER and BER. However, no correlation was found between tumour tissue and blood cells. In conclusion, although comet assay based approaches to measure BER/NER phenotypes are feasible and promising, more work is needed to further optimize their application in human biomonitoring and intervention studies.
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Affiliation(s)
- Amaya Azqueta
- Department of Pharmacology and Toxicology, University of Navarra, C/Irunlarrea 1, 31009 Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
| | - Sabine A S Langie
- VITO - Sustainable Health, Mol, Belgium; Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Elisa Boutet-Robinet
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Susan Duthie
- School of Pharmacy and Life Sciences, The Robert Gordon University, Riverside East, Garthdee Road, Aberdeen, AB10 7GJ, United Kingdom
| | - Carina Ladeira
- H&TRC- Health & Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, Av. D. João II, lote 4.69.01, Parque das Nações, 1990-096 Lisboa, Portugal; Centro de Investigação e Estudos em Saúde Pública, Escola Nacional de Saúde Pública, Universidade Nova de Lisboa, Portugal
| | - Peter Møller
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark
| | - Andrew R Collins
- Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway
| | - Roger W L Godschalk
- Department of Pharmacology & Toxicology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, The Netherlands
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25
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Salvestrini V, Sell C, Lorenzini A. Obesity May Accelerate the Aging Process. Front Endocrinol (Lausanne) 2019; 10:266. [PMID: 31130916 PMCID: PMC6509231 DOI: 10.3389/fendo.2019.00266] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 04/10/2019] [Indexed: 12/27/2022] Open
Abstract
Lines of evidence from several studies have shown that increases in life expectancy are now accompanied by increased disability rate. The expanded lifespan of the aging population imposes a challenge on the continuous increase of chronic disease. The prevalence of overweight and obesity is increasing at an alarming rate in many parts of the world. Further to increasing the onset of metabolic imbalances, obesity leads to reduced life span and affects cellular and molecular processes in a fashion resembling aging. Nine key hallmarks of the aging process have been proposed. In this review, we will review these hallmarks and discuss pathophysiological changes that occur with obesity, that are similar to or contribute to those that occur during aging. We present and discuss the idea that obesity, in addition to having disease-specific effects, may accelerate the rate of aging affecting all aspects of physiology and thus shortening life span and health span.
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Affiliation(s)
- Valentina Salvestrini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Christian Sell
- Department of Pathology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Antonello Lorenzini
- Department of Biomedical and Neuromotor Sciences, Biochemistry Unit, University of Bologna, Bologna, Italy
- *Correspondence: Antonello Lorenzini
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26
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Choi YS, Park JH, Lee JH, Yoon JK, Yun BH, Park JH, Seo SK, Sung HJ, Kim HS, Cho S, Lee BS. Association Between Impairment of DNA Double Strand Break Repair and Decreased Ovarian Reserve in Patients With Endometriosis. Front Endocrinol (Lausanne) 2018; 9:772. [PMID: 30622513 PMCID: PMC6308303 DOI: 10.3389/fendo.2018.00772] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022] Open
Abstract
Background: Repair of DNA double strand break (DSB) is an important mechanism for maintaining genetic stability during a DNA damage event. Although, a growing body of recent evidence suggests that DNA DSBs and related repair mechanisms may be important in ovarian aging and in various cancers, there are few reports in endometriosis. We, therefore, examined expression levels of genes pertaining to DNA DSB repair in patients with endometriosis to assess the potential effects on ovarian reserves. Materials and methods: A total of 69 women undergoing laparoscopic surgery for endometriosis and other benign conditions was included; endometriosis group (n = 38) vs. controls (n = 31). DNA DSBs in endometrial and ovarian tissues of both groups were compared via immunohistochemistry, aimed at γ-H2AX expression. To gauge genotoxin-induced DNA DSBs in endometrial stromal cells, γ-H2AX expression was determined by western blot after H2O2 treatment of cultured endometrial stromal cells (endometriosis group and controls) and Ishikawa cell-line cultures. Endometrial and ovarian tissue levels of BRCA1, BRCA2, Rad51, and ATM (ataxia-telangiectasia mutated) mRNA expression were also compared. Correlations between expression levels of genes of interest and serum anti-müllerian hormone (AMH) levels were assessed as well. Results: Expression of γ-H2AX in immunostained endometrial and ovarian tissue preparations was greater in the endometriosis group, compared with controls. After H2O2 treatment, γ-H2AX expression levels were also significantly greater in cultured stromal cells of the endometriosis group and in the Ishikawa cell line than in controls. Endometrial expression of BRCA1 and Rad51 mRNA proved significantly lower in the endometriosis group (vs. controls), as did ovarian expression of BRCA1 and BRCA2 mRNA. Serum AMH concentration showed a significant correlation with ovarian BRCA1 mRNA expression in women with endometriosis (p = 0.03). Conclusions: In women with endometriosis, expression levels of various genes implicated in DSB repair are decreased and ovarian BRCA1 expression correlates with.
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Affiliation(s)
- Young Sik Choi
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Ji Hyun Park
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Hoon Lee
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Jeong-Kee Yoon
- Department of Medical Engineering, Yonsei University College of Medicine, Seoul, South Korea
| | - Bo Hyon Yun
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Joo Hyun Park
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Seok Kyo Seo
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Hak-Joon Sung
- Department of Medical Engineering, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyun-Soo Kim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Hyun-Soo Kim
| | - SiHyun Cho
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- SiHyun Cho
| | - Byung Seok Lee
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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