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Jeong H, Ko Y, Kim KW, Lee JS, Seo S, Kim SY, Hong YS, Kim JE, Kim TW. Longitudinal changes in body composition during palliative systemic chemotherapy and survival outcomes in metastatic colorectal cancer. World J Gastrointest Oncol 2025; 17:103479. [DOI: 10.4251/wjgo.v17.i5.103479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/22/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND In patients with metastatic colorectal cancer, chemotherapy may lead to changes in body composition, including skeletal muscle quantity and quality, and body fat area and distribution. Longitudinal follow-up data in a homogeneous population are required to understand these changes better.
AIM To comprehensively evaluate changes in body composition and their prognostic value in patients with metastatic colorectal cancer undergoing palliative chemotherapy.
METHODS This retrospective study included patients with recurrent or metastatic colorectal cancer who received palliative chemotherapy between 2008 and 2017. Computed tomography scans were analyzed at multiple time points (before each new chemotherapy regimen and after discontinuing all chemotherapy). Body composition was analyzed from each scan using artificial intelligence software (AID-UTM, iAID Inc.), and its association with survival was evaluated through time-dependent Cox regression to adjust for time-varying effects.
RESULTS This analysis included 1805 patients, with a median age at diagnosis of 57 years, and 62% were male. At first-line chemotherapy initiation, 4.7%, 30.9%, 36.5%, and 37.1% of the patients had sarcopenia, myosteatosis, and visceral and subcutaneous obesity, respectively. During treatment, approximately 54.5% of the patients experienced significant changes in body composition, with 9.1% and 19.2% developing new sarcopenia and myosteatosis, respectively. Sarcopenia and myosteatosis were associated with poorer survival outcomes [hazard ratio (HR) for sarcopenia, 2.55 (95%CI: 2.06-3.16, P < 0.001; HR for myosteatosis, 2.37 (95%CI: 2.00-2.82), P < 0.001]. In contrast, visceral and subcutaneous obesity were associated with improved survival [HR for visceral obesity, 0.69 (95%CI: 0.57-0.82), P < 0.001; HR for subcutaneous obesity, 0.78 (95%CI: 0.64-0.95), P = 0.015], with no negative impacts observed at higher fat levels. These changes correlated with end-of-life survival time.
CONCLUSION Abnormalities and body composition changes were frequently observed during palliative chemotherapy for advanced colorectal cancer; myosteatosis was common. Comprehensive body composition assessment offers valuable prognostic insights without requiring additional testing.
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Affiliation(s)
- Hyehyun Jeong
- Department of Oncology, Asan Medical Center, Seoul 05505, South Korea
| | - Yousun Ko
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, South Korea
| | - Kyung Won Kim
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea
| | - Ji Sung Lee
- Clinical Research Center, Asan Medical Center, Asan Medical Center, Seoul 05505, South Korea
| | - Seyoung Seo
- Department of Oncology, Asan Medical Center, Seoul 05505, South Korea
| | - Sun Young Kim
- Department of Oncology, Asan Medical Center, Seoul 05505, South Korea
| | - Yong Sang Hong
- Department of Oncology, Asan Medical Center, Seoul 05505, South Korea
| | - Jeong Eun Kim
- Department of Oncology, Asan Medical Center, Seoul 05505, South Korea
| | - Tae Won Kim
- Department of Oncology, Asan Medical Center, Seoul 05505, South Korea
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Silva J, Azevedo T, Ferreira R, Neuparth MJ, Seixas F, Ginja M, Pires MJ, Faustino-Rocha AI, Duarte JA, Oliveira PA. The Impact of a Western Diet and Resistance Training in a Rat Model of Mammary Cancer. Life (Basel) 2025; 15:250. [PMID: 40003658 PMCID: PMC11856199 DOI: 10.3390/life15020250] [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: 01/16/2025] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
This study aimed to investigate the impact of a Western diet and resistance training on cardiac remodeling in a rat model of chemically induced mammary cancer. Fifty-six female Wistar rats were randomly assigned to one of eight experimental groups, evaluating the impact of Western and standard diets, exercise and sedentarism, and the induction of mammary cancer. Mammary cancer was induced via the intraperitoneal administration of N-methyl-N-nitrosourea (MNU) (50 mg/kg) at seven weeks of age. The resistance training protocol consisted of ladder climbing three times per week for an 18-week period, with a gradual increase in load over time. At the end of the 20-week experimental period, the animals were anesthetized and underwent echocardiography. Subsequently, the animals were euthanized, and organs and visceral adipose tissue (VAT) were collected and analyzed. A histopathological examination was performed on the mammary tumors. The Western diet increased relative VAT and contributed to cardiovascular and tumor-related changes, including an increase in interventricular septum thickness (IVS) and left ventricle posterior wall thickness (LVPW) at end-systole. Exercise reduced fat accumulation, improved cardiac performance, and helped regulate cardiovascular function, as indicated by a higher eccentricity index (EI) in the WD+EX group compared to the WD group. The WD was associated with increased VAT accumulation and initially delayed tumor initiation; however, over time, it contributed to bigger tumor aggressiveness. This diet also delayed tumor initiation but increased LVPW. Exercise, when combined with a WD, accelerated tumorigenesis, malignant transformation and invasiveness, resulted in the higher prevalence of invasive tumors. These findings underscore the complex and potentially compounding effects of diet and exercise on cancer progression.
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Affiliation(s)
- Jessica Silva
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (J.S.); (T.A.); (M.G.); (M.J.P.); (P.A.O.)
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000-801 Vila Real, Portugal
| | - Tiago Azevedo
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (J.S.); (T.A.); (M.G.); (M.J.P.); (P.A.O.)
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Science-AL4AnimalS, UTAD, 5000-801 Vila Real, Portugal;
- Mountain Research Center (CIMO), Associated Laboratory for Sustainability and Technology in Inland Regions (SusTEC), Polytechnique Institute of Bragança (IPB), 5300-253 Bragança, Portugal
| | - Rita Ferreira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Maria J. Neuparth
- Research Center in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports—University of Porto (FADEUP), 4200-450 Porto, Portugal;
- Laboratory for Integrative and Translational Research in Population Health (ITR), 4200-450 Porto, Portugal
- Toxicology Research Unit (TOXRUN), University Institute of Health Sciences, CESPU, 4585-116 Gandra, Portugal
| | - Fernanda Seixas
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Science-AL4AnimalS, UTAD, 5000-801 Vila Real, Portugal;
| | - Mário Ginja
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (J.S.); (T.A.); (M.G.); (M.J.P.); (P.A.O.)
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Science-AL4AnimalS, UTAD, 5000-801 Vila Real, Portugal;
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
| | - Maria J. Pires
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (J.S.); (T.A.); (M.G.); (M.J.P.); (P.A.O.)
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
| | - Ana I. Faustino-Rocha
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (J.S.); (T.A.); (M.G.); (M.J.P.); (P.A.O.)
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000-801 Vila Real, Portugal
- Department of Zootechnics, School of Sciences and Technology, University of Évora, 7004-516 Évora, Portugal
- Comprehensive Health Research Center (CHRC), University of Évora, 7004-516 Évora, Portugal
| | - José Alberto Duarte
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, University Institute of Health Sciences—CESPU, 4585-116 Gandra, Portugal;
- UCIBIO—Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal
| | - Paula A. Oliveira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (J.S.); (T.A.); (M.G.); (M.J.P.); (P.A.O.)
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
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Kompella P, Wang G, Durrett RE, Lai Y, Marin C, Liu Y, Habib SL, DiGiovanni J, Vasquez KM. Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots. Nat Commun 2024; 15:6213. [PMID: 39043652 PMCID: PMC11266421 DOI: 10.1038/s41467-024-50006-8] [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: 01/31/2023] [Accepted: 06/26/2024] [Indexed: 07/25/2024] Open
Abstract
Obesity is associated with increased cancer risk, yet the underlying mechanisms remain elusive. Obesity-associated cancers involve disruptions in metabolic and cellular pathways, which can lead to genomic instability. Repetitive DNA sequences capable of adopting alternative DNA structures (e.g., H-DNA) stimulate mutations and are enriched at mutation hotspots in human cancer genomes. However, it is not known if obesity impacts DNA repeat-mediated endogenous mutation hotspots. We address this gap by measuring mutation frequencies in obese and normal-weight transgenic reporter mice carrying either a control human B-DNA- or an H-DNA-forming sequence (from a translocation hotspot in c-MYC in Burkitt lymphoma). Here, we discover that H-DNA-induced DNA damage and mutations are elevated in a tissue-specific manner, and DNA repair efficiency is reduced in obese mice compared to those on the control diet. These findings elucidate the impact of obesity on cancer-associated endogenous mutation hotspots, providing mechanistic insight into the link between obesity and cancer.
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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, Austin, TX, USA
| | - Guliang Wang
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA
| | - Russell E Durrett
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
| | - Yanhao Lai
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA
| | - Celeste Marin
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA
| | - Yuan Liu
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA
| | - Samy L Habib
- South Texas Veterans Health Care System, San Antonio, TX, USA
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA
| | - Karen M Vasquez
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA.
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Attia SM, Alshamrani AA, Ahmad SF, Albekairi NA, Nadeem A, Attia MSM, Ansari MA, Almutairi F, Bakheet SA. Dulaglutide reduces oxidative DNA damage and hypermethylation in the somatic cells of mice fed a high-energy diet by restoring redox balance, inflammatory responses, and DNA repair gene expressions. J Biochem Mol Toxicol 2024; 38:e23764. [PMID: 38963172 DOI: 10.1002/jbt.23764] [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: 02/05/2024] [Revised: 06/06/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide's expediency in treating obesity and its associated complications.
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Affiliation(s)
- Sabry M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ali A Alshamrani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sheikh F Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Norah A Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohamed S M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mushtaq A Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Faris Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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5
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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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Supruniuk E, Baczewska M, Żebrowska E, Maciejczyk M, Lauko KK, Dajnowicz-Brzezik P, Milewska P, Knapp P, Zalewska A, Chabowski A. Redox Biomarkers and Matrix Remodeling Molecules in Ovarian Cancer. Antioxidants (Basel) 2024; 13:200. [PMID: 38397798 PMCID: PMC10885995 DOI: 10.3390/antiox13020200] [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: 12/12/2023] [Revised: 01/24/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Ovarian cancer (OC) has emerged as the leading cause of death due to gynecological malignancies among women. Oxidative stress and metalloproteinases (MMPs) have been shown to influence signaling pathways and afflict the progression of carcinogenesis. Therefore, the assessment of matrix-remodeling and oxidative stress intensity can determine the degree of cellular injury and often the severity of redox-mediated chemoresistance. The study group comprised 27 patients with serous OC of which 18% were classified as Federation of Gynecology and Obstetrics (FIGO) stages I/II, while the rest were diagnosed grades III/IV. The control group comprised of 15 ovarian tissue samples. The results were compared with genetic data from The Cancer Genome Atlas. Nitro-oxidative stress, inflammation and apoptosis biomarkers were measured colorimetrically/fluorometrically or via real-time PCR in the primary ovarian tumor and healthy tissue. Stratification of patients according to FIGO stages revealed that high-grade carcinoma exhibited substantial alterations in redox balance, including the accumulation of protein glycoxidation and lipid peroxidation products. TCGA data demonstrated only limited prognostic usefulness of the studied genes. In conclusion, high-grade serous OC is associated with enhanced tissue oxidative/nitrosative stress and macromolecule damage that could not be overridden by the simultaneously augmented measures of antioxidant defense. Therefore, it can be assumed that tumor cells acquire adaptive mechanisms that enable them to withstand the potential toxic effects of elevated reactive oxygen species.
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Affiliation(s)
- Elżbieta Supruniuk
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
| | - Marta Baczewska
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A Street, 15-276 Bialystok, Poland; (M.B.); (P.K.)
| | - Ewa Żebrowska
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland;
| | - Kamil Klaudiusz Lauko
- Students’ Scientific Club ‘Biochemistry of Civilization Diseases’ at the Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland;
| | - Patrycja Dajnowicz-Brzezik
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
| | - Patrycja Milewska
- Biobank, Medical University of Bialystok, Waszyngtona 13 Street, 15-269 Bialystok, Poland;
| | - Paweł Knapp
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A Street, 15-276 Bialystok, Poland; (M.B.); (P.K.)
- University Oncology Center, University Clinical Hospital in Bialystok, Marii Skłodowskiej-Curie 24A Street, 15-276 Bialystok, Poland
| | - Anna Zalewska
- Independent Laboratory of Experimental Dentistry, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A, 15-276 Bialystok, Poland;
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (E.Ż.); (P.D.-B.); (A.C.)
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7
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Mazzarella L, Falvo P, Adinolfi M, Tini G, Gatti E, Piccioni R, Bonetti E, Gavilán E, Valli D, Gruszka A, Bodini M, Gallo B, Orecchioni S, de Michele G, Migliaccio E, Duso BA, Roerink S, Stratton M, Bertolini F, Alcalay M, Dellino GI, Pelicci PG. High-Fat Diet Promotes Acute Promyelocytic Leukemia through PPARδ-Enhanced Self-renewal of Preleukemic Progenitors. Cancer Prev Res (Phila) 2024; 17:59-75. [PMID: 37956420 DOI: 10.1158/1940-6207.capr-23-0246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/04/2023] [Accepted: 11/09/2023] [Indexed: 11/15/2023]
Abstract
Risk and outcome of acute promyelocytic leukemia (APL) are particularly worsened in obese-overweight individuals, but the underlying molecular mechanism is unknown. In established mouse APL models (Ctsg-PML::RARA), we confirmed that obesity induced by high-fat diet (HFD) enhances leukemogenesis by increasing penetrance and shortening latency, providing an ideal model to investigate obesity-induced molecular events in the preleukemic phase. Surprisingly, despite increasing DNA damage in hematopoietic stem cells (HSC), HFD only minimally increased mutational load, with no relevant impact on known cancer-driving genes. HFD expanded and enhanced self-renewal of hematopoietic progenitor cells (HPC), with concomitant reduction in long-term HSCs. Importantly, linoleic acid, abundant in HFD, fully recapitulates the effect of HFD on the self-renewal of PML::RARA HPCs through activation of peroxisome proliferator-activated receptor delta, a central regulator of fatty acid metabolism. Our findings inform dietary/pharmacologic interventions to counteract obesity-associated cancers and suggest that nongenetic factors play a key role. PREVENTION RELEVANCE Our work informs interventions aimed at counteracting the cancer-promoting effect of obesity. On the basis of our study, individuals with a history of chronic obesity may still significantly reduce their risk by switching to a healthier lifestyle, a concept supported by evidence in solid tumors but not yet in hematologic malignancies. See related Spotlight, p. 47.
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Affiliation(s)
| | - Paolo Falvo
- IRCCS European Institute of Oncology, Milan, Italy
| | | | - Giulia Tini
- IRCCS European Institute of Oncology, Milan, Italy
| | - Elena Gatti
- IRCCS European Institute of Oncology, Milan, Italy
| | | | | | | | - Debora Valli
- IRCCS European Institute of Oncology, Milan, Italy
| | | | | | | | | | | | | | - Bruno A Duso
- IRCCS European Institute of Oncology, Milan, Italy
| | - Sophie Roerink
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
| | - Mike Stratton
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
| | | | - Myriam Alcalay
- IRCCS European Institute of Oncology, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan
| | - Gaetano Ivan Dellino
- IRCCS European Institute of Oncology, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan
| | - Pier Giuseppe Pelicci
- IRCCS European Institute of Oncology, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan
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Okus F, Yuzbasioglu D, Unal F. Molecular docking study of frequently used food additives for selected targets depending on the chromosomal abnormalities they cause. Toxicology 2024; 502:153716. [PMID: 38159899 DOI: 10.1016/j.tox.2023.153716] [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: 10/26/2023] [Revised: 12/26/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
Food additives (FAs) (flavor enhancers, sweeteners, etc.) protect foods during storage and transportation, making them attractive to consumers. Today, while the desire to access natural foods is increasing, the chemicals added to foods have started to be questioned. In this respect, genotoxicity tests have gained importance. Studies show that some food additives may have genotoxic risks. Previous studies carried out in our laboratory also revealed genotoxic effects of Monopotassium glutamate (MPG), Monosodium glutamate (MSG), Magnesium diglutamate (MDG) as flavor enhancers; Potassium benzoate (PB), Potassium sorbate (PS), Sodium benzoate (SB), Sodium sorbate (SS) as preservatives; Acesulfame potassium (ACE-K), Xylitol (XYL) as sweeteners. In this study, we determined the interactions of these food additives with ATM and p53 proteins, which are activated in the cell due to genotoxic effects, and with DNA by employing the molecular docking method for the first time. Among the food additives, SB (-4.307) for ATM, XYL (-4.629) for p53, and XYL (-4.927) for DNA showed the highest affinity. Therefore, flexible docking (IFD) scores were determined for SB, XYL, and MDG from flavor enhancers. The potential binding modes of the food additives to target molecules' possible inhibition mechanisms were determined by molecular docking. Thus, new information was obtained to show how these additives cause chromosomal abnormalities.
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Affiliation(s)
- Fatma Okus
- Graduate School of Natural and Applied Sciences, Gazi University, Teknikokullar, Ankara, Türkiye
| | - Deniz Yuzbasioglu
- Genetic Toxicology Laboratory, Department of Biology, Science Faculty, Gazi University, Teknikokullar, Ankara, Türkiye.
| | - Fatma Unal
- Genetic Toxicology Laboratory, Department of Biology, Science Faculty, Gazi University, Teknikokullar, Ankara, Türkiye
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Xu Q, del Mundo IMA, Zewail-Foote M, Luke BT, Vasquez KM, Kowalski J. MoCoLo: a testing framework for motif co-localization. Brief Bioinform 2024; 25:bbae019. [PMID: 38521050 PMCID: PMC10960634 DOI: 10.1093/bib/bbae019] [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: 10/26/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 03/25/2024] Open
Abstract
Sequence-level data offers insights into biological processes through the interaction of two or more genomic features from the same or different molecular data types. Within motifs, this interaction is often explored via the co-occurrence of feature genomic tracks using fixed-segments or analytical tests that respectively require window size determination and risk of false positives from over-simplified models. Moreover, methods for robustly examining the co-localization of genomic features, and thereby understanding their spatial interaction, have been elusive. We present a new analytical method for examining feature interaction by introducing the notion of reciprocal co-occurrence, define statistics to estimate it and hypotheses to test for it. Our approach leverages conditional motif co-occurrence events between features to infer their co-localization. Using reverse conditional probabilities and introducing a novel simulation approach that retains motif properties (e.g. length, guanine-content), our method further accounts for potential confounders in testing. As a proof-of-concept, motif co-localization (MoCoLo) confirmed the co-occurrence of histone markers in a breast cancer cell line. As a novel analysis, MoCoLo identified significant co-localization of oxidative DNA damage within non-B DNA-forming regions that significantly differed between non-B DNA structures. Altogether, these findings demonstrate the potential utility of MoCoLo for testing spatial interactions between genomic features via their co-localization.
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Affiliation(s)
- Qi Xu
- Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78712, USA
- Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Imee M A del Mundo
- Dell Pediatric Research Institute, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78723, USA
| | - Maha Zewail-Foote
- Department of Chemistry and Biochemistry, Southwestern University, Georgetown, TX, 78626, USA
| | - Brian T Luke
- Bioinformatics and Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21701, USA
| | - Karen M Vasquez
- Dell Pediatric Research Institute, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78723, USA
| | - Jeanne Kowalski
- Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA
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10
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Jiang Y, Shen Z, Xu J, Zhu J, Wang H, Chen W, Sun Y, Yang Q. The impact of female BMI on sperm DNA damage repair ability of oocytes and early embryonic development potential in intracytoplasmic sperm injection cycles. Front Endocrinol (Lausanne) 2023; 14:1168010. [PMID: 37780615 PMCID: PMC10534975 DOI: 10.3389/fendo.2023.1168010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/06/2023] [Indexed: 10/03/2023] Open
Abstract
Background Obesity adversely influences the quality of oocytes and embryos and can affect DNA repair in embryos, leading to reproductive issues. However, the effects of body mass index (BMI) on DNA repair ability in oocytes during intracytoplasmic sperm injection (ICSI) cycles have not yet been investigated. Therefore, this retrospective study aimed to analyze the influence of sperm DNA damage on embryo development and reproductive outcomes in overweight/obese and normal-weight women in ICSI cycles. Methods A total of 1,141 patients who received the first fresh ICSI cycle treatments were recruited from July 2017 to July 2021. Based on the BMI of the women, all patients were divided into normal weight (18.5≤BMI<25 kg/m2; n=824; 72.22%) and overweight/obese (BMI≥25 kg/m2; n=317; 27.78%) groups. Furthermore, according to the sperm DNA fragmentation index (DFI), these two groups were subdivided into two subgroups: DFI<30% and DFI≥30%. Results In the normal-weight women group, the embryonic development and reproductive outcomes of ICSI cycles were not statistically different between the two subgroups (DFI<30% and DFI≥30%). However, in the overweight/obese women group, couples with a sperm DFI≥30% had a significantly lower fertilization rate (76% vs. 72.7%; p=0.027), cleavage rate (98.7% vs. 97.2%; p=0.006), and high-quality embryo rate (67.8% vs. 62.6%; p=0.006) than couples with a sperm DFI<30%. Conclusion When injected sperm with high DFI into the oocytes of overweight/obese women, resulting in lower fertilization, cleavage, and high-quality embryo rates in ICSI cycles, and the decreased early developmental potential of embryos from overweight/obese patients may be caused by the diminished capacity of oocytes to repair sperm DNA damage.
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Affiliation(s)
- Yuqing Jiang
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhaoyang Shen
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianmin Xu
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Zhu
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huan Wang
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenhui Chen
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingpu Sun
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingling Yang
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Bocian-Jastrzębska A, Malczewska-Herman A, Kos-Kudła B. Role of Leptin and Adiponectin in Carcinogenesis. Cancers (Basel) 2023; 15:4250. [PMID: 37686525 PMCID: PMC10486522 DOI: 10.3390/cancers15174250] [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: 07/31/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Hormones produced by adipocytes, leptin and adiponectin, are associated with the process of carcinogenesis. Both of these adipokines have well-proven oncologic potential and can affect many aspects of tumorigenesis, from initiation and primary tumor growth to metastatic progression. Involvement in the formation of cancer includes interactions with the tumor microenvironment and its components, such as tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix and matrix metalloproteinases. Furthermore, these adipokines participate in the epithelial-mesenchymal transition and connect to angiogenesis, which is critical for cancer invasiveness and cancer cell migration. In addition, an enormous amount of evidence has demonstrated that altered concentrations of these adipocyte-derived hormones and the expression of their receptors in tumors are associated with poor prognosis in various types of cancer. Therefore, leptin and adiponectin dysfunction play a prominent role in cancer and impact tumor invasion and metastasis in different ways. This review clearly and comprehensively summarizes the recent findings and presents the role of leptin and adiponectin in cancer initiation, promotion and progression, focusing on associations with the tumor microenvironment and its components as well as roles in the epithelial-mesenchymal transition and angiogenesis.
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Affiliation(s)
- Agnes Bocian-Jastrzębska
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland; (A.M.-H.); (B.K.-K.)
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12
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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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Rosiek V, Bocian-Jastrzębska A, Kos-Kudła B. Selected Serum Biomarkers (Leptin, Chromogranin A, CA19-9, CEA) in Patients with Pancreatic Neuroendocrine Neoplasm and Associations with Metabolic Syndrome. Cancers (Basel) 2023; 15:cancers15082348. [PMID: 37190276 DOI: 10.3390/cancers15082348] [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: 02/19/2023] [Revised: 04/13/2023] [Accepted: 04/15/2023] [Indexed: 05/17/2023] Open
Abstract
Metabolic abnormalities are well-known risk factors for many cancers, even though no clearly established link with pancreatic neuroendocrine neoplasms (PanNENs) has yet been investigated. This research aimed to assess the serum levels of leptin, chromogranin A (CgA), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) in patients with PanNENs and to search for associations between PanNENs, these selected serum biomarkers, and metabolic abnormalities in the form of metabolic syndrome (MS). Second, we aimed to investigate whether MS increases the risk of PanNENs. The serum concentrations of biomarkers, metabolic parameters (glucose, cholesterol, triglycerides), and anthropometric measurements (weight, height, BMI) were assessed in 106 patients with PanNENs and 40 healthy volunteers. Patients with PanNENs showed higher serum concentrations of CA19-9, CEA, and CgA in comparison to controls (p < 0.001, p = 0.042, and p = 0.025, respectively). Statistically significant differences in CEA levels were found in PanNENs patients with MS (p = 0.043). PanNENs patients with a BMI ≥ 25 kg/m2 and who were female exhibited significantly higher leptin levels (p < 0.001 and p = 0.013, respectively). Additionally, this study reflects the importance of determining markers. Future research should focus on understanding the impact of metabolic disturbances on PanNENs and accounting for the relationship between PanNENs and MS, such as other malignancies.
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Affiliation(s)
- Violetta Rosiek
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinology, Medical University of Silesia, 40-514 Katowice, Poland
| | - Agnes Bocian-Jastrzębska
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinology, Medical University of Silesia, 40-514 Katowice, Poland
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinology, Medical University of Silesia, 40-514 Katowice, Poland
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Stępień S, Olczyk P, Gola J, Komosińska-Vassev K, Mielczarek-Palacz A. The Role of Selected Adipocytokines in Ovarian Cancer and Endometrial Cancer. Cells 2023; 12:cells12081118. [PMID: 37190027 DOI: 10.3390/cells12081118] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/06/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Due to their multidirectional influence, adipocytokines are currently the subject of numerous intensive studies. Significant impact applies to many processes, both physiological and pathological. Moreover, the role of adipocytokines in carcinogenesis seems particularly interesting and not fully understood. For this reason, ongoing research focuses on the role of these compounds in the network of interactions in the tumor microenvironment. Particular attention should be drawn to cancers that remain challenging for modern gynecological oncology-ovarian and endometrial cancer. This paper presents the role of selected adipocytokines, including leptin, adiponectin, visfatin, resistin, apelin, chemerin, omentin and vaspin in cancer, with a particular focus on ovarian and endometrial cancer, and their potential clinical relevance.
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Affiliation(s)
- Sebastian Stępień
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland
| | - Paweł Olczyk
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland
| | - Aleksandra Mielczarek-Palacz
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland
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15
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Wang X, Shi G, Fan S, Ma J, Yan Y, Wang M, Tang X, Lv P, Zhang Y. Targeted delivery of food functional ingredients in precise nutrition: design strategy and application of nutritional intervention. Crit Rev Food Sci Nutr 2023; 64:7854-7877. [PMID: 36999956 DOI: 10.1080/10408398.2023.2193275] [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] [Indexed: 04/01/2023]
Abstract
With the high incidence of chronic diseases, precise nutrition is a safe and efficient nutritional intervention method to improve human health. Food functional ingredients are an important material base for precision nutrition, which have been researched for their application in preventing diseases and improving health. However, their poor solubility, stability, and bad absorption largely limit their effect on nutritional intervention. The establishment of a stable targeted delivery system is helpful to enhance their bioavailability, realize the controlled release of functional ingredients at the targeted action sites in vivo, and provide nutritional intervention approaches and methods for precise nutrition. In this review, we summarized recent studies about the types of targeted delivery systems for the delivery of functional ingredients and their digestion fate in the gastrointestinal tract, including emulsion-based delivery systems and polymer-based delivery systems. The building materials, structure, size and charge of the particles in these delivery systems were manipulated to fabricate targeted carriers. Finally, the targeted delivery systems for food functional ingredients have gained some achievements in nutritional intervention for inflammatory bowel disease (IBD), liver disease, obesity, and cancer. These findings will help in designing fine targeted delivery systems, and achieving precise nutritional intervention for food functional ingredients on human health.
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Affiliation(s)
- Xu Wang
- Hebei Food Inspection and Research Institute, Hebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Shijiazhuang, China
- Department of Cell Biology, Cardiovascular Medical Science Center, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Guohua Shi
- Hebei Food Inspection and Research Institute, Hebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Shijiazhuang, China
| | - Sufang Fan
- Hebei Food Inspection and Research Institute, Hebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Shijiazhuang, China
| | - Junmei Ma
- Hebei Food Inspection and Research Institute, Hebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Shijiazhuang, China
| | - Yonghuan Yan
- Hebei Food Inspection and Research Institute, Hebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Shijiazhuang, China
- School of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Mengtian Wang
- Hebei Food Inspection and Research Institute, Hebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Shijiazhuang, China
- School of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Xiaozhi Tang
- College of Food Science and Engineering, Collaborative Innovation Center for Modern Grain Circulation and Safety, Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, China
| | - Pin Lv
- Department of Cell Biology, Cardiovascular Medical Science Center, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, China
| | - Yan Zhang
- Hebei Food Inspection and Research Institute, Hebei Food Safety Key Laboratory, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Hebei Engineering Research Center for Special Food Safety and Health, Shijiazhuang, China
- School of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
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8-Oxoguanine DNA Glycosylase 1 Upregulation as a Risk Factor for Obesity and Colorectal Cancer. Int J Mol Sci 2023; 24:ijms24065488. [PMID: 36982562 PMCID: PMC10052644 DOI: 10.3390/ijms24065488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/10/2023] [Accepted: 03/12/2023] [Indexed: 03/15/2023] Open
Abstract
DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)—a DNA repair enzyme—may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants (p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients (p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients (p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.
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Mangani D, Yang D, Anderson AC. Learning from the nexus of autoimmunity and cancer. Immunity 2023; 56:256-271. [PMID: 36792572 PMCID: PMC9986833 DOI: 10.1016/j.immuni.2023.01.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/13/2023] [Accepted: 01/19/2023] [Indexed: 02/16/2023]
Abstract
The immune system plays critical roles in both autoimmunity and cancer, diseases at opposite ends of the immune spectrum. Autoimmunity arises from loss of T cell tolerance against self, while in cancer, poor immunity against transformed self fails to control tumor growth. Blockade of pathways that preserve self-tolerance is being leveraged to unleash immunity against many tumors; however, widespread success is hindered by the autoimmune-like toxicities that arise in treated patients. Knowledge gained from the treatment of autoimmunity can be leveraged to treat these toxicities in patients. Further, the understanding of how T cell dysfunction arises in cancer can be leveraged to induce a similar state in autoreactive T cells. Here, we review what is known about the T cell response in autoimmunity and cancer and highlight ways in which we can learn from the nexus of these two diseases to improve the application, efficacy, and management of immunotherapies.
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Affiliation(s)
- Davide Mangani
- Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Universita della Svizzera Italiana, Bellinzona 6500, Switzerland.
| | - Dandan Yang
- Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA
| | - Ana C Anderson
- Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA.
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18
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The higher body mass index is associated with a lower somatic mutation dependency in hepatocellular carcinoma. INFORMATICS IN MEDICINE UNLOCKED 2023. [DOI: 10.1016/j.imu.2023.101187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
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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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20
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Bohm MS, Sipe LM, Pye ME, Davis MJ, Pierre JF, Makowski L. The role of obesity and bariatric surgery-induced weight loss in breast cancer. Cancer Metastasis Rev 2022; 41:673-695. [PMID: 35870055 PMCID: PMC9470652 DOI: 10.1007/s10555-022-10050-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/06/2022] [Indexed: 02/07/2023]
Abstract
Obesity is a complex metabolic condition considered a worldwide public health crisis, and a deeper mechanistic understanding of obesity-associated diseases is urgently needed. Obesity comorbidities include many associated cancers and are estimated to account for 20% of female cancer deaths in the USA. Breast cancer, in particular, is associated with obesity and is the focus of this review. The exact causal links between obesity and breast cancer remain unclear. Still, interactions have emerged between body mass index, tumor molecular subtype, genetic background, and environmental factors that strongly suggest obesity influences the risk and progression of certain breast cancers. Supportive preclinical research uses various diet-induced obesity models to demonstrate that weight loss, via dietary interventions or changes in energy expenditure, reduces the onset or progression of breast cancers. Ongoing and future studies are now aimed at elucidating the underpinning mechanisms behind weight-loss-driven observations to improve therapy and outcomes in patients with breast cancer and reduce risk. This review aims to summarize the rapidly emerging literature on obesity and weight loss strategies with a focused discussion of bariatric surgery in both clinical and preclinical studies detailing the complex interactions between metabolism, immune response, and immunotherapy in the setting of obesity and breast cancer.
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Affiliation(s)
- Margaret S Bohm
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Laura M Sipe
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Madeline E Pye
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Matthew J Davis
- Division of Bariatric Surgery, Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Joseph F Pierre
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
- Department of Nutritional Sciences, College of Agriculture and Life Science, The University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Liza Makowski
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- College of Medicine, UTHSC Center for Cancer Research, The University of Tennessee Health Science Center, Cancer Research Building Room 322, 19 S Manassas Street, Memphis, TN, 38163, USA.
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21
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Obesity: The Fat Tissue Disease Version of Cancer. Cells 2022; 11:cells11121872. [PMID: 35741001 PMCID: PMC9221301 DOI: 10.3390/cells11121872] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 02/06/2023] Open
Abstract
Obesity is a disease with high potential for fatality. It perfectly fits the disease definition, as cancer does. This is because it damages body structure and functions, both mechanically and biologically, and alters physical, mental, and social health. In addition, it shares many common morbid characteristics with the most feared disease, cancer. For example, it is influenced by a sophisticated interaction between a person’s genetics, the environment, and an increasing number of other backgrounds. Furthermore, it displays abnormal cell growth and proliferation events, only limited to white fat, resulting in adipose tissue taking up an increasing amount of space within the body. This occurs through fat “metastases” and via altered signaling that further aggravates the pathology of obesity by inducing ubiquitous dishomeostasis. These metastases can be made graver by angiogenesis, which might boost diseased tissue growth. More common features with cancer include its progressive escalation through different levels of severity and its possibility of re-onset after recovery. Despite all these similarities with cancer, obesity is substantially less agitating for most people. Thus, the ideas proposed herein could have utility to sensitize the public opinion about the hard reality of obesity. This is increasingly needed, as the obesity pandemic has waged a fierce war against our bodies and society in general, while there is still doubt about whether it is a real disease or not. Hence, raising public consciousness to properly face health issues is crucial to improving our health instead of gaining weight unhealthily. It is obviously illogical to fight cancer extremely seriously on the one hand and to consider dying with obesity as self-inflicted on the other. In fact, obesity merits a top position among the most lethal diseases besides cancer.
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22
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Kavec MJ, Urbanova M, Makovicky P, Opattová A, Tomasova K, Kroupa M, Kostovcikova K, Siskova A, Navvabi N, Schneiderova M, Vymetalkova V, Vodickova L, Vodicka P. Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases MUTYH and hOGG1 in Colorectal Cancer Patients. Int J Mol Sci 2022; 23:ijms23105704. [PMID: 35628513 PMCID: PMC9145200 DOI: 10.3390/ijms23105704] [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: 04/14/2022] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 02/05/2023] Open
Abstract
Oxidative stress, oxidative DNA damage and resulting mutations play a role in colorectal carcinogenesis. Impaired equilibrium between DNA damage formation, antioxidant status, and DNA repair capacity is responsible for the accumulation of genetic mutations and genomic instability. The lesion-specific DNA glycosylases, e.g., hOGG1 and MUTYH, initiate the repair of oxidative DNA damage. Hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome) with germline mutations causing a loss-of-function in base excision repair glycosylases, serve as straight forward evidence on the role of oxidative DNA damage and its repair. Altered or inhibited function of above glycosylases result in an accumulation of oxidative DNA damage and contribute to the adenoma-adenocarcinoma transition. Oxidative DNA damage, unless repaired, often gives rise G:C > T:A mutations in tumor suppressor genes and proto-oncogenes with subsequent occurrence of chromosomal copy-neutral loss of heterozygosity. For instance, G>T transversions in position c.34 of a KRAS gene serves as a pre-screening tool for MUTYH-associated polyposis diagnosis. Since sporadic colorectal cancer represents more complex and heterogenous disease, the situation is more complicated. In the present study we focused on the roles of base excision repair glycosylases (hOGG1, MUTYH) in colorectal cancer patients by investigating tumor and adjacent mucosa tissues. Although we found downregulation of both glycosylases and significantly lower expression of hOGG1 in tumor tissues, accompanied with G>T mutations in KRAS gene, oxidative DNA damage and its repair cannot solely explain the onset of sporadic colorectal cancer. In this respect, other factors (especially microenvironment) per se or in combination with oxidative DNA damage warrant further attention. Base excision repair characteristics determined in colorectal cancer tissues and their association with disease prognosis have been discussed as well.
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Affiliation(s)
- Miriam J. Kavec
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, 140 59 Prague, Czech Republic
| | - Marketa Urbanova
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic;
| | - Pavol Makovicky
- Department of Biology, Faculty of Education, J Selye University, Bratislavska 3322, 945 01 Komarno, Slovakia;
| | - Alena Opattová
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic;
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00 Pilsen, Czech Republic
| | - Kristyna Tomasova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00 Pilsen, Czech Republic
| | - Michal Kroupa
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00 Pilsen, Czech Republic
| | - Klara Kostovcikova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic;
| | - Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic;
| | - Nazila Navvabi
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00 Pilsen, Czech Republic
| | - Michaela Schneiderova
- Department of Surgery, General University Hospital in Prague, First Medical Faculty, Charles University, Katerinska 1660, 128 00 Prague, Czech Republic;
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic;
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00 Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic;
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00 Pilsen, Czech Republic
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; (M.J.K.); (A.O.); (K.T.); (M.K.); (A.S.); (N.N.); (V.V.); (L.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic;
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, 323 00 Pilsen, Czech Republic
- Correspondence: ; Tel.: +420-241062694
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23
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Huang C, Sun Y, Liao SR, Chen ZX, Lin HF, Shen WZ. Suppression of Berberine and Probiotics ( in vitro and in vivo) on the Growth of Colon Cancer With Modulation of Gut Microbiota and Butyrate Production. Front Microbiol 2022; 13:869931. [PMID: 35572672 PMCID: PMC9096942 DOI: 10.3389/fmicb.2022.869931] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/29/2022] [Indexed: 12/24/2022] Open
Abstract
Background and Objective An increasing number of evidence has revealed that the gut microbiome functions in immunity, inflammation, metabolism, and homeostasis and is considered to be crucial due to its balance between human health and diseases such as cancer, leading to the emergence of treatments that target intestinal microbiota. Probiotics are one of them. However, many challenges remain regarding the effects of probiotics in cancer treatment. Berberine (BBR), a natural extract of Rhizoma Coptidis and extensively used in the treatment of gastrointestinal diseases, has been found to have antitumor effects in vivo and in vitro by many recent studies, but its definite mechanisms are still unclear. This study aimed to explore the inhibitory effect of BBR and probiotics on the growth of colon cancer cells in vitro and in vivo, and the regulatory influence on the gut microbiome and butyrate production. Methods Colon cancer cell line HT29 was used to establish a xenograft model of nude mice and an in vitro model. A total of 44 nude mice and HT29 cells were divided into control, model, model + BBR, model + probiotics, and model + combination of BBR with probiotics (CBPs). Live combined Bifidobacterium, Lactobacillus, and Enterococcus powder (LCBLEP) was used as a probiotic preparation. LCBLEP was cultured in the liquid medium under anaerobic conditions (the number of viable bacteria should reach 1 × 108CFU), and the supernatant was collected, and it is called probiotic supernatant (PS). Model + BBR and model + probiotics groups were treated with BBR and LCBLEP or PS for 4 weeks in vivo or 48, 72, and 96 h in vitro, respectively. Tumor volume or cell proliferation was measured. Gut microbiota was pyrosequenced using a 16S rDNA amplicon. HDAC1 mRNA level in HT29 cells and sodium butyrate (SB) expression in the serum of mice was detected by QPCR and ELISA. Results The treatment of BBR and CBP reduced the growth of neoplasms in mice to a different extent (p > 0.05), especially at 14 days. The inhibitory effect of LCBLEP on tumor growth was more significant, especially at 11-21 days (p < 0.05). Inhibition of BBR on in vitro proliferation was concentration-dependent. The suppression of 75% probiotic supernatant (PS) on the proliferation was the most significant. The supplement of LCBLEP significantly increased the richness and evenness of the gut microbe. BBR dramatically increased the abundance of Bacteroidetes and Proteobacteria, with reduced Ruminococcus, followed by the LCBLEP. The LCBLEP reduced the relative abundance of Verrucomicrobia and Akkermansia, and the CBP also promoted the relative level of Bacteroidetes but reduced the level of Verrucomicrobia and Akkermansia. BBR and LCBLEP or CBP improved the alpha and beta diversity and significantly affected the biomarker and metabolic function of the gut microbe in nude mice with colon cancer. The level of HDAC1 mRNA was reduced in HT29 cells treated with BBR or PS (p < 0.05), the mice treated with BBR revealed a significantly increased concentration of SB in serum (p < 0.05), and the inhibitory effect of SB on the proliferation of HT29 cells was stronger than panobinostat and TSA. Conclusion Although the combination of BBR and probiotics has no advantage in inhibiting tumor growth compared with the drug alone, BBR can be used as a regulator of the intestinal microbiome similar to the probiotics by mediating the production of SB during reducing the growth of colon cancer.
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Affiliation(s)
- Chao Huang
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Shenzhen University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
| | - Ying Sun
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Shenzhen University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
| | - Sheng-Rong Liao
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Shenzhen University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
| | - Zhao-Xin Chen
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Shenzhen University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
| | - Han-Feng Lin
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Shenzhen University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
| | - Wei-Zeng Shen
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Shenzhen University, People's Hospital of Shenzhen Baoan District, Shenzhen, China
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Effectiveness of an Intervention Programme on Adherence to the Mediterranean Diet in a Preschool Child: A Randomised Controlled Trial. Nutrients 2022; 14:nu14081536. [PMID: 35458098 PMCID: PMC9025428 DOI: 10.3390/nu14081536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/03/2022] [Accepted: 04/05/2022] [Indexed: 01/23/2023] Open
Abstract
Background: The Mediterranean diet is considered one of the dietary patterns with the most accumulated scientific evidence on health benefits. In children, it has positive effects in the prevention of obesity and cardiovascular diseases, as well as in the prevention of diabetes. We aimed to evaluate the medium-term efficacy of an intervention programme, targeting adherence to the Mediterranean diet among preschool children. Methods: In a randomised, parallel trial of participants aged 3–5 years, a school garden was attended in the experimental group, and in the control group, the usual content on the human body and health were taught. Adherence to the Mediterranean diet was assessed using the KIDMED questionnaire, controlling for weight, height, body mass index (BMI) and socio-demographic variables. Results: A reduction in BMI was found in the experimental group after one year and at the end of the follow-up period. In the overall score obtained in the KIDMED survey, a statistical trend was found between the two groups (p = 0.076). In multivariate analysis, consumption of pulses more than once a week’ was predictive of improved diet quality, with an Odds Ratio (OR) in the experimental group of 1.382 (95% CI 1.126–1.695; p = 0.009). Conclusions: The experimental approach improved the quality of the participants’ diet, increasing adherence to the Mediterranean diet due to increased consumption of plant-based protein.
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25
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Man J, Zhang T, Yin X, Chen H, Zhang Y, Zhang X, Chen J, Yang X, Lu M. Spatiotemporal Trends of Colorectal Cancer Mortality Due to Low Physical Activity and High Body Mass Index From 1990 to 2019: A Global, Regional and National Analysis. Front Med (Lausanne) 2022; 8:800426. [PMID: 35083251 PMCID: PMC8784601 DOI: 10.3389/fmed.2021.800426] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 12/10/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Understanding the spatiotemporal trends of colorectal cancer (CRC) deaths caused by low physical activity (LPA) and high body mass index (BMI) is essential for the prevention and control of CRC. We assessed patterns of LPA and high BMI-induced CRC deaths from 1990 to 2019 at global, regional, and national levels. Methods: Data on CRC deaths due to LPA and high BMI was downloaded from the Global Burden of Disease 2019 Study. We calculated estimated annual percentage change (EAPC) to quantify spatiotemporal trends in the CRC age-standardized mortality rate (ASMR) due to LPA and high BMI. Results: In 2019, CRC deaths due to LPA and high BMI were estimated as 58.66 thousand and 85.88 thousand, and the corresponding ASMRs were 0.77/100,000 and 1.07/100,000, with EAPCs of−0.39 [95% confidence interval (CI):−0.49,−0.29] and 0.64[95% CI: 0.57, 0.71] from 1990 to 2019 respectively. Since 1990, the ASMR of CRC attributable to LPA and high BMI has been on the rise in many geographic regions, especially in low middle and middle sociodemographic index (SDI) regions. Thirteen countries had a significant downward trend in CRC ASMR attributed to LPA, with EAPCs < −1. And, only 4 countries had a significant downward trend in CRC ASMR attributable to high BMI, with EAPCs < −1. Countries with a higher baseline burden in 1990 and a higher SDI in 2019 had a faster decline in ASMR due to high BMI and LPA. Conclusions: The burden of CRC caused by LPA and high BMI is on the rise in many countries. Countries should adopt a series of measures to control the local prevalence of obesity and LPA in order to reduce disease burden, including CRC.
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Affiliation(s)
- Jinyu Man
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tongchao Zhang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaolin Yin
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hui Chen
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yuan Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xuening Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jiaqi Chen
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaorong Yang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ming Lu
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Li J, Zhang C, Li L, Hu X, Jia Y, Huang Y, Lyu T, Wang X, Guo X. Folate deficiency enhances the in vitro genotoxicity of bile acids in human colon and liver cells. Mutagenesis 2021; 37:34-43. [PMID: 34791379 DOI: 10.1093/mutage/geab041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 11/14/2021] [Indexed: 11/13/2022] Open
Abstract
Obese subjects have a high baseline of genotoxic stress, but the underlying mechanism is poorly understood. Given that obesity is associated with high bile acids (BA) and low folate, we aimed to determine the interactive effect of folate deficient or supplementation to the genotoxicity and cytotoxicity of BA in human colon and liver cells. NCM460 and L-02 cells were cultured in folate deficient (22.6 nM) and replete (2260 nM) RPMI 1640 medium with or without 50 μM deoxycholic acid (DCA) or lithocholic acid (LCA) for 7 days. Moreover, these cells were cultured in folate supplemented (5.65, 11.3 and 22.6 μM) and standard (2.26 μM) medium with 200 μM DCA or LCA for 7 days. Genotoxicity and cytotoxicity were measured using the cytokinesis-block micronucleus cytome assay. Our results showed that under folate-replete condition, 50 μM DCA or LCA significantly increased the rate of micronuclei in NCM460 and L-02 cells. Significantly, the micronuclei-inducing effect of 50 μM DCA or LCA was further enhanced by folate deficiency. Interestingly, folate supplementation exerted a dose-dependent manner to significantly decrease the rates of micronuclei, nucleoplasmic bridges, nuclear buds, apoptosis and necrosis induced by 200 μM DCA or LCA in NCM460 and L-02 cells. In conclusion, the genotoxicity of moderate BA (50 μM) was exacerbated by folate deficiency and folate supplementation could efficiently protect cells against the genotoxicity and cytotoxicity of high BA (200 μM).
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Affiliation(s)
- Jianfei Li
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China
| | - Cheng Zhang
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China
| | - Lingzhi Li
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China
| | - Xueqin Hu
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China
| | - Yizhen Jia
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China
| | - Yanan Huang
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China
| | - Ting Lyu
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China
| | - Xu Wang
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China.,Yunnan Environmental Mutagen Society, Kunming, Yunnan, China
| | - Xihan Guo
- School of Life Sciences, Yunnan Normal University, Kunming, Yunnan, China.,Yunnan Environmental Mutagen Society, Kunming, Yunnan, China
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27
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Luciano TF, De Souza CT, Pinho RA, Marques SDO, Luiz GP, Tramontin NDS, Silveira PCLD, de Andrade VM, Muller AP. Effects of Zingiber officinale extract supplementation on metabolic and genotoxic parameters in diet-induced obesity in mice. Br J Nutr 2021; 126:970-981. [PMID: 33323139 DOI: 10.1017/s0007114520005073] [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] [Indexed: 12/07/2022]
Abstract
Obesity is an epidemic associated with many diseases. The nutraceutical Zingiber officinale (ZO) is a potential treatment for obesity; however, the molecular effects are unknown. Swiss male mice were fed a high-fat diet (59 % energy from fat) for 16 weeks to generate a diet-induced obesity (DIO) model and then divided into the following groups: standard diet + vehicle; standard diet + ZO; DIO + vehicle and DIO + ZO. Those in the ZO groups were supplemented with 400 mg/kg per d of ZO extract (oral administration) for 35 d. The animals were euthanised, and blood, quadriceps, epididymal fat pad and hepatic tissue were collected. DIO induced insulin resistance, proinflammatory cytokines, oxidative stress and DNA damage in different tissues. Treatment with ZO improved insulin sensitivity as well as decreased serum TAG, without changes in body weight or adiposity index. TNF-α and IL-1β levels were lower in the liver and quadriceps in the DIO + ZO group compared with the DIO group. ZO treatment reduced the reactive species and oxidative damage to proteins, lipids and DNA in blood and liver in obese animals. The endogenous antioxidant activity was higher in the quadriceps of DIO + ZO. These results in the rat model of DIO may indicate ZO as an adjuvant on obesity treatment.
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Affiliation(s)
- Thaís Fernandes Luciano
- Laboratory of Biomedicine Translational, University of Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Claudio Teodoro De Souza
- Department of Internal Medicine, Medicine School, Juiz de Fora Federal University, Juiz de Fora, MG, Brazil
| | - Ricardo Aurino Pinho
- Laboratory of Exercise Biochemistry in Health, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil
| | | | - Gabriel Paulino Luiz
- Laboratory of Biomedicine Translational, University of Extremo Sul Catarinense, Criciúma, SC, Brazil
| | | | | | - Vanessa Moraes de Andrade
- Laboratory of Biomedicine Translational, University of Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Alexandre Pastoris Muller
- Laboratory of Biomedicine Translational, University of Extremo Sul Catarinense, Criciúma, SC, Brazil
- Pharmacology Department, Federal University of Santa Catarina, Florianópolis, SC, Brazil
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Kirsch-Volders M, Fenech M. Inflammatory cytokine storms severity may be fueled by interactions of micronuclei and RNA viruses such as COVID-19 virus SARS-CoV-2. A hypothesis. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2021; 788:108395. [PMID: 34893160 PMCID: PMC8479308 DOI: 10.1016/j.mrrev.2021.108395] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 12/25/2022]
Abstract
In this review we bring together evidence that (i) RNA viruses are a cause of chromosomal instability and micronuclei (MN), (ii) those individuals with high levels of lymphocyte MN have a weakened immune response and are more susceptible to RNA virus infection and (iii) both RNA virus infection and MN formation can induce inflammatory cytokine production. Based on these observations we propose a hypothesis that those who harbor elevated frequencies of MN within their cells are more prone to RNA virus infection and are more likely, through combined effects of leakage of self-DNA from MN and RNA from viruses, to escalate pro-inflammatory cytokine production via the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) and the Senescence Associated Secretory Phenotype (SASP) mechanisms to an extent that is unresolvable and therefore confers high risk of causing tissue damage by an excessive and overtly toxic immune response. The corollaries from this hypothesis are (i) those with abnormally high MN frequency are more prone to infection by RNA viruses; (ii) the extent of cytokine production and pro-inflammatory response to infection by RNA viruses is enhanced and possibly exceeds threshold levels that may be unresolvable in those with elevated MN levels in affected organs; (iii) reduction of MN frequency by improving nutrition and life-style factors increases resistance to RNA virus infection and moderates inflammatory cytokine production to a level that is immunologically efficacious and survivable.
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Affiliation(s)
- Micheline Kirsch-Volders
- Laboratory for Cell Genetics, Department Biology, Faculty of Sciences and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
| | - Michael Fenech
- Genome Health Foundation, North Brighton, SA, 5048, Australia; Clinical and Health Sciences, University of South Australia, SA, 5000, Australia; Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
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Abstract
AbstractThe world is in the grip of an obesity pandemic, with tripling of obesity rates since 1975; it is predicted that one-third of people on Earth will be obese by 2025. The health consequences of obesity are primarily thought to be related to cardiometabolic disorders such as diabetes and cardiovascular diseases. It is less well appreciated that obesity has been related to at least 13 different cancers and in future, (with increasing control over tobacco misuse and infections), obesity will be the main cause of cancers. While this is an area of active research, there are large gaps in the definition of what is an obesity related cancer (JRC) and more importantly, what are the underlying mechanisms. To an extent, this is due to the controversy on what constitutes “unhealthy obesity” which is further related to the causes of obesity. This narrative review examines the causes and measurement of obesity, the types of obesity-related cancers and possible mechanisms. The information has wide implications ranging from prevention, screening, prognosis and therapeutic strategies. Obesity related cancers should be an area of high-priority research. Oncologists can contribute by spreading awareness and instituting management measures for individual patients in their care.
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Affiliation(s)
- Ajit Venniyoor
- National Oncology Centre, The Royal Hospital, Muscat, Sultanate of Oman
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30
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Behavioral Risk Factors and Risk of Early-Onset Colorectal Cancer: Review of the Mechanistic and Observational Evidence. CURRENT COLORECTAL CANCER REPORTS 2021. [DOI: 10.1007/s11888-021-00465-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Li G, Meng H, Bai Y, Wei W, Feng Y, Li M, Li H, He M, Zhang X, Wei S, Li Y, Guo H. DNA methylome analysis identifies BMI-related epigenetic changes associated with non-small cell lung cancer susceptibility. Cancer Med 2021; 10:3770-3781. [PMID: 33939316 PMCID: PMC8178488 DOI: 10.1002/cam4.3906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/16/2021] [Accepted: 03/30/2021] [Indexed: 12/20/2022] Open
Abstract
Background Body mass index (BMI) has been reported to be inversely associated with incident risk of non‐small cell lung cancer (NSCLC). However, the underlying mechanism is still unclear. This study aimed to investigate the role of DNA methylation in the relationship between BMI and NSCLC. Methods We carried out a genome‐wide DNA methylation study of BMI in peripheral blood among 2266 Chinese participants by using Illumina Methylation arrays. For the BMI‐related DNA methylation changes, their associations with NSCLC risk were further analyzed and their mediation effects on BMI‐NSCLC association were also evaluated. Results The methylation levels of four CpGs (cg12593793, cg17061862, cg11024682, and cg06500161, annotated to LMNA, ZNF143, SREBF1, and ABCG1, respectively) were found to be significantly associated with BMI. Methylation levels of cg12593793, cg11024682, and cg06500161 were observed to be inversely associated with NSCLC risk [OR (95%CI) =0.22 (0.16, 0.31), 0.39 (0.30, 0.50), and 0.66 (0.53, 0.82), respectively]. Additionally, cg11024682 in SREBF1 and cg06500161 in ABCG1 mediated 45.3% and 19.5% of the association between BMI and decreased NSCLC risk, respectively. Conclusions In this study, we identified four DNA methylation sites associated with BMI in the Chinese populations at the genome‐wide significant level. We also found that the BMI‐related methylations of SREBF1 and ABCG1 could mediate about a quintile‐to‐half of the effect of BMI on reduced NSCLC risk, which adds a potential mechanism underlying this association.
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Affiliation(s)
- Guyanan Li
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hua Meng
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yansen Bai
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Wei
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yue Feng
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengying Li
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hang Li
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meian He
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaomin Zhang
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Wei
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yangkai Li
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huan Guo
- Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Rey F, Messa L, Pandini C, Launi R, Barzaghini B, Micheletto G, Raimondi MT, Bertoli S, Cereda C, Zuccotti GV, Cancello R, Carelli S. Transcriptome Analysis of Subcutaneous Adipose Tissue from Severely Obese Patients Highlights Deregulation Profiles in Coding and Non-Coding Oncogenes. Int J Mol Sci 2021; 22:1989. [PMID: 33671464 PMCID: PMC7922682 DOI: 10.3390/ijms22041989] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023] Open
Abstract
Obesity is a major risk factor for a large number of secondary diseases, including cancer. Specific insights into the role of gender differences and secondary comorbidities, such as type 2 diabetes (T2D) and cancer risk, are yet to be fully identified. The aim of this study is thus to find a correlation between the transcriptional deregulation present in the subcutaneous adipose tissue of obese patients and the oncogenic signature present in multiple cancers, in the presence of T2D, and considering gender differences. The subcutaneous adipose tissue (SAT) of five healthy, normal-weight women, five obese women, five obese women with T2D and five obese men were subjected to RNA-sequencing, leading to the identification of deregulated coding and non-coding RNAs, classified for their oncogenic score. A panel of DE RNAs was validated via Real-Time PCR and oncogene expression levels correlated the oncogenes with anthropometrical parameters, highlighting significant trends. For each analyzed condition, we identified the deregulated pathways associated with cancer, the prediction of possible prognosis for different cancer types and the lncRNAs involved in oncogenic networks and tissues. Our results provided a comprehensive characterization of oncogenesis correlation in SAT, providing specific insights into the possible molecular targets implicated in this process. Indeed, the identification of deregulated oncogenes also in SAT highlights hypothetical targets implicated in the increased oncogenic risk in highly obese subjects. These results could shed light on new molecular targets to be specifically modulated in obesity and highlight which cancers should receive the most attention in terms of better prevention in obesity-affected patients.
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Affiliation(s)
- Federica Rey
- Department of Biomedical and Clinical Sciences “L. Sacco”, School of Medicine, University of Milano, Via Grassi 74, 20157 Milano, Italy; (F.R.); (R.L.); (G.V.Z.)
- Pediatric Clinical Research Centre Fondazione “Romeo ed Enrica Invernizzi”, University of Milano, Via G.B. Grassi 74, 20157 Milano, Italy
| | - Letizia Messa
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy; (L.M.); (B.B.); (M.T.R.)
| | - Cecilia Pandini
- Genomic and Post-Genomic Centre, IRCCS Mondino Foundation, 27100 Pavia, Italy; (C.P.); (C.C.)
| | - Rossella Launi
- Department of Biomedical and Clinical Sciences “L. Sacco”, School of Medicine, University of Milano, Via Grassi 74, 20157 Milano, Italy; (F.R.); (R.L.); (G.V.Z.)
- Pediatric Clinical Research Centre Fondazione “Romeo ed Enrica Invernizzi”, University of Milano, Via G.B. Grassi 74, 20157 Milano, Italy
| | - Bianca Barzaghini
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy; (L.M.); (B.B.); (M.T.R.)
| | - Giancarlo Micheletto
- Department of Pathophysiology and Transplantation, INCO and Department of General Surgery, Istituto Clinico Sant’Ambrogio, University of Milan, Via Francesco Sforza 35, 20122 Milano, Italy;
| | - Manuela Teresa Raimondi
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy; (L.M.); (B.B.); (M.T.R.)
| | - Simona Bertoli
- Obesity Unit—Laboratory of Nutrition and Obesity Research, Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Via Ariosto 9, 20145 Milano, Italy; (S.B.); (R.C.)
- International Center for the Assessment of Nutritional Status (ICANS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milano, Italy
| | - Cristina Cereda
- Genomic and Post-Genomic Centre, IRCCS Mondino Foundation, 27100 Pavia, Italy; (C.P.); (C.C.)
| | - Gian Vincenzo Zuccotti
- Department of Biomedical and Clinical Sciences “L. Sacco”, School of Medicine, University of Milano, Via Grassi 74, 20157 Milano, Italy; (F.R.); (R.L.); (G.V.Z.)
- Pediatric Clinical Research Centre Fondazione “Romeo ed Enrica Invernizzi”, University of Milano, Via G.B. Grassi 74, 20157 Milano, Italy
- Department of Pediatrics, Children’s Hospital “V. Buzzi”, Via Lodovico Castelvetro 32, 20154 Milano, Italy
| | - Raffaella Cancello
- Obesity Unit—Laboratory of Nutrition and Obesity Research, Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Via Ariosto 9, 20145 Milano, Italy; (S.B.); (R.C.)
| | - Stephana Carelli
- Department of Biomedical and Clinical Sciences “L. Sacco”, School of Medicine, University of Milano, Via Grassi 74, 20157 Milano, Italy; (F.R.); (R.L.); (G.V.Z.)
- Pediatric Clinical Research Centre Fondazione “Romeo ed Enrica Invernizzi”, University of Milano, Via G.B. Grassi 74, 20157 Milano, Italy
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D'Amico AM, Vasquez KM. The multifaceted roles of DNA repair and replication proteins in aging and obesity. DNA Repair (Amst) 2021; 99:103049. [PMID: 33529944 DOI: 10.1016/j.dnarep.2021.103049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
Efficient mechanisms for genomic maintenance (i.e., DNA repair and DNA replication) are crucial for cell survival. Aging and obesity can lead to the dysregulation of genomic maintenance proteins/pathways and are significant risk factors for the development of cancer, metabolic disorders, and other genetic diseases. Mutations in genes that code for proteins involved in DNA repair and DNA replication can also exacerbate aging- and obesity-related disorders and lead to the development of progeroid diseases. In this review, we will discuss the roles of various DNA repair and replication proteins in aging and obesity as well as investigate the possible mechanisms by which aging and obesity can lead to the dysregulation of these proteins and pathways.
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Affiliation(s)
- Alexandra M D'Amico
- 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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Abstract
PURPOSE OF REVIEW Hyperadiposity, as present in obesity, is a substantial threat to cancer risk and prognosis. Studies that have investigated the link between obesity and tumor progression have proposed several mechanistic frameworks, yet, these mechanisms are not fully defined. Further, a comprehensive understanding of how these various mechanisms may interact to create a dynamic disease state is lacking in the current literature. RECENT FINDINGS Recent work has begun to explore not only discrete mechanisms by which obesity may promote tumor growth (for instance, metabolic and growth factor functions of insulin; inflammatory cytokines; adipokines; and others), but also how these putative tumor-promoting factors may interact. SUMMARY This review will highlight the present understanding of obesity, as it relates to tumor development and progression. First, we will introduce the impact of obesity in cancer within the dynamic tumor microenvironment, which will serve as a theme to frame this review. The core of this review will discuss recently proposed mechanisms that implicate obesity in tumor progression, including chronic inflammation and the role of pro-inflammatory cytokines, adipokines, hormones, and genetic approaches. Furthermore, we intend to offer current insight in targeting adipose tissue during the development of cancer prevention and treatment strategies.
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Affiliation(s)
- Andin Fosam
- Department of Internal Medicine
- Department of Cellular & Molecular Physiology, School of Medicine Yale University, TAC, New Haven, Connecticut, USA
| | - Rachel J Perry
- Department of Internal Medicine
- Department of Cellular & Molecular Physiology, School of Medicine Yale University, TAC, New Haven, Connecticut, USA
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35
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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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Fu Y, Yuan SS, Zhang LJ, Ji ZL, Quan XJ. Atonal bHLH transcription factor 1 is an important factor for maintaining the balance of cell proliferation and differentiation in tumorigenesis. Oncol Lett 2020; 20:2595-2605. [PMID: 32782577 PMCID: PMC7400680 DOI: 10.3892/ol.2020.11833] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 09/06/2019] [Indexed: 12/15/2022] Open
Abstract
Establishing the link between cellular processes and oncogenesis may aid the elucidation of targeted and effective therapies against tumor cell proliferation and metastasis. Previous studies have investigated the mechanisms involved in maintaining the balance between cell proliferation, differentiation and migration. There is increased interest in determining the conditions that allow cancer stem cells to differentiate as well as the identification of molecules that may serve as novel drug targets. Furthermore, the study of various genes, including transcription factors, which serve a crucial role in cellular processes, may present a promising direction for future therapy. The present review described the role of the transcription factor atonal bHLH transcription factor 1 (ATOH1) in signaling pathways in tumorigenesis, particularly in cerebellar tumor medulloblastoma and colorectal cancer, where ATOH1 serves as an oncogene or tumor suppressor, respectively. Additionally, the present review summarized the associated therapeutic interventions for these two types of tumors and discussed novel clinical targets and approaches.
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Affiliation(s)
- Ying Fu
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Sha-Sha Yuan
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Li-Jie Zhang
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Zhi-Li Ji
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Xiao-Jiang Quan
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China.,Laboratory of Brain Development, Institut du Cerveau et de la Moelle Épinière, Hôpital Pitié-Salpêtrière, 75013 Paris, France
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Turbitt WJ, Rosean CB, Weber KS, Norian LA. Obesity and CD8 T cell metabolism: Implications for anti-tumor immunity and cancer immunotherapy outcomes. Immunol Rev 2020; 295:203-219. [PMID: 32157710 PMCID: PMC7416819 DOI: 10.1111/imr.12849] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/21/2020] [Accepted: 02/24/2020] [Indexed: 12/12/2022]
Abstract
Obesity is an established risk factor for many cancers and has recently been found to alter the efficacy of T cell-based immunotherapies. Currently, however, the effects of obesity on immunometabolism remain unclear. Understanding these associations is critical, given the fact that T cell metabolism is tightly linked to effector function. Thus, any obesity-associated changes in T cell bioenergetics are likely to drive functional changes at the cellular level, alter the metabolome and cytokine/chemokine milieu, and impact cancer immunotherapy outcomes. Here, we provide a brief overview of T cell metabolism in the presence and absence of solid tumor growth and summarize current literature regarding obesity-associated changes in T cell function and bioenergetics. We also discuss recent findings related to the impact of host obesity on cancer immunotherapy outcomes and present potential mechanisms by which T cell metabolism may influence therapeutic efficacy. Finally, we describe promising pharmaceutical therapies that are being investigated for their ability to improve CD8 T cell metabolism and enhance cancer immunotherapy outcomes in patients, regardless of their obesity status.
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Affiliation(s)
- William J. Turbitt
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
| | | | - K. Scott Weber
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah
| | - Lyse A. Norian
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, Alabama
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama
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Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients. Int J Mol Sci 2020; 21:ijms21072473. [PMID: 32252452 PMCID: PMC7177219 DOI: 10.3390/ijms21072473] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.
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Trumble BC, Finch CE. THE EXPOSOME IN HUMAN EVOLUTION: FROM DUST TO DIESEL. THE QUARTERLY REVIEW OF BIOLOGY 2019; 94:333-394. [PMID: 32269391 PMCID: PMC7141577 DOI: 10.1086/706768] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Global exposures to air pollution and cigarette smoke are novel in human evolutionary history and are associated with about 16 million premature deaths per year. We investigate the history of the human exposome for relationships between novel environmental toxins and genetic changes during human evolution in six phases. Phase I: With increased walking on savannas, early human ancestors inhaled crustal dust, fecal aerosols, and spores; carrion scavenging introduced new infectious pathogens. Phase II: Domestic fire exposed early Homo to novel toxins from smoke and cooking. Phases III and IV: Neolithic to preindustrial Homo sapiens incurred infectious pathogens from domestic animals and dense communities with limited sanitation. Phase V: Industrialization introduced novel toxins from fossil fuels, industrial chemicals, and tobacco at the same time infectious pathogens were diminishing. Thereby, pathogen-driven causes of mortality were replaced by chronic diseases driven by sterile inflammogens, exogenous and endogenous. Phase VI: Considers future health during global warming with increased air pollution and infections. We hypothesize that adaptation to some ancient toxins persists in genetic variations associated with inflammation and longevity.
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Affiliation(s)
- Benjamin C Trumble
- School of Human Evolution & Social Change and Center for Evolution and Medicine, Arizona State University Tempe, Arizona 85287 USA
| | - Caleb E Finch
- Leonard Davis School of Gerontology and Dornsife College, University of Southern California Los Angeles, California 90089-0191 USA
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