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Qian Y, Bu Z, Qin Y, Qian S, Qin L, Zhou S, Wang Q, Xian L, Hu L, Xiong Y, Zhang Y, Wang C. Exploring the role of adipokines in exercise-induced inhibition of tumor growth. SPORTS MEDICINE AND HEALTH SCIENCE 2025; 7:143-156. [PMID: 39811408 PMCID: PMC11726049 DOI: 10.1016/j.smhs.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 03/04/2024] [Accepted: 03/18/2024] [Indexed: 01/16/2025] Open
Abstract
The integration of exercise prescriptions into cancer adjuvant therapy presents challenges stemming from the ambiguity surrounding the precise mechanism through which exercise intervention mitigates the risk of hepatocellular carcinoma (HCC) mortality and recurrence. Elucidation of this specific mechanism has substantial social and clinical implications. In this study, tumor-bearing mice engaged in voluntary wheel running exhibited a notable decrease in tumor growth, exceeding 30%. Microarray analysis revealed an upregulation of cytokine-related pathways as a potential explanation for this effect. The inclusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to enhance tumor cell proliferation, while the absence of GM-CSF resulted in a marked inhibition of tumor cell growth. The findings suggest that exercise-induced serum from mice can impede the proliferation of mouse tumor cells, with the adipokine chemerin inhibiting the growth factor GM-CSF. Additionally, exercise was found to stimulate chemerin secretion by brown adipose tissue. Chemerin suppression led to a reduction in the inhibition of tumor cell proliferation. The results of this study suggest that exercise may stimulate the release of adipokines from brown adipose tissue, transport them through the blood to the distant tumor microenvironment, and downregulate GM-CSF expression, alleviating tumor immunosuppression in the tumor microenvironment, thereby inhibiting at HCC progression. These findings provide a theoretical basis for incorporating exercise prescription into cancer treatment.
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Affiliation(s)
- Yu Qian
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Zhenglong Bu
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Yang Qin
- School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China
| | - Shiyuan Qian
- West China School of Public Health, Sichuan University, Chengdu, China
| | - Lu Qin
- School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China
| | - Siqi Zhou
- School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China
| | - Qingda Wang
- School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China
| | - Longjun Xian
- School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China
| | - Lei Hu
- School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China
| | - Yimei Xiong
- School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China
| | - Yingying Zhang
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Chun Wang
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
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Braschler L, Nikolaidis PT, Thuany M, Chlíbková D, Rosemann T, Weiss K, Wilhelm M, Knechtle B. Physiology and Pathophysiology of Marathon Running: A narrative Review. SPORTS MEDICINE - OPEN 2025; 11:10. [PMID: 39871014 PMCID: PMC11772678 DOI: 10.1186/s40798-025-00810-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 12/30/2024] [Indexed: 01/29/2025]
Abstract
BACKGROUND Marathon training and running have many beneficial effects on human health and physical fitness; however, they also pose risks. To date, no comprehensive review regarding both the benefits and risks of marathon running on different organ systems has been published. MAIN BODY The aim of this review was to provide a comprehensive review of the benefits and risks of marathon training and racing on different organ systems. A predefined search strategy including keywords (e.g., marathon, cardiovascular system, etc.) and free text search was used. Articles covering running regardless of sex, age, performance level, and event type (e.g., road races, mountain marathons) were considered, whereas articles examining only cycling, triathlon, stress-tests or other sports were excluded. In total, we found 1021 articles in PubMed, Scopus, and Google Scholar, of which 329 studies were included in this review. Overall, marathon training offers several benefits for different organ systems and reduces all-cause mortality. As such, it improves cardiovascular risk factors, leads to favorable cardiac adaptations, enhances lung function, and improves quality of life in chronic kidney disease patients. It also enhances gastrointestinal mobility and reduces the risk of specific tumors such as colorectal cancer and hepatocellular carcinoma. Marathon training enhances bone health and skeletal muscle metabolism. It further positively affects hematopoiesis and cytotoxic abilities of natural killer cells, and may act neuroprotective on a long-term basis. After a marathon, changes in biomarkers suggesting pathological events in certain organ systems such as cardiovascular, renal, gastrointestinal, liver, hematological, immune, musculoskeletal, central nervous, and endocrine systems can often be observed. Mostly, these changes are limited to 1-3 days post-race and usually normalize within a week. Moreover, marathon running poses the risk of serious adverse events such as sudden cardiac death or acute liver failure. Concerning lung function, a decrease after a marathon race was observed. Acute kidney injury, as well as electrolyte imbalances, are relatively common amongst marathon finishers. Many runners complain of gastrointestinal symptoms during or after long-distance running. Many runners suffer from running-related musculoskeletal injuries often impairing performance. A marathon is often accompanied by an acute inflammatory response with transient immunosuppression, making runners susceptible to infections. Also, hormonal alterations such as increased cortisol levels or decreased testosterone levels immediately after a race are observed. Disturbances in sleep patterns are commonly found in marathon runners leading up to or directly after the race. CONCLUSION All in all, marathon training is generally safe for human health and individual organ systems. Considering the high popularity of marathon running, these findings supply athletes, coaches, sports scientists, and sports medicine practitioners with practical applications. Further large-scale studies examining long-term effects on the cardiovascular, renal, and other system are needed.
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Affiliation(s)
- Lorin Braschler
- Centre for Rehabilitation and Sports Medicine, Inselspital, University Hospital of Bern, University of Bern, Bern, Switzerland
| | | | - Mabliny Thuany
- Department of Physical Education, State University of Para, Pará, Brazil
| | - Daniela Chlíbková
- Brno University of Technology, Centre of Sport Activities, Brno, Czechia
| | - Thomas Rosemann
- Institute of Primary Care, University of Zurich, Zurich, Switzerland
| | - Katja Weiss
- Institute of Primary Care, University of Zurich, Zurich, Switzerland
| | - Matthias Wilhelm
- Centre for Rehabilitation and Sports Medicine, Inselspital, University Hospital of Bern, University of Bern, Bern, Switzerland
| | - Beat Knechtle
- Institute of Primary Care, University of Zurich, Zurich, Switzerland.
- Medbase St. Gallen Am Vadianplatz, Vadianstrasse 26, 9001, St. Gallen, Switzerland.
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Huyen VT, Echizen K, Yamagishi R, Kumagai M, Nonaka Y, Kodama T, Ando T, Yano M, Takada N, Takasugi M, Kamachi F, Ohtani N. Regular exercise suppresses steatosis-associated liver cancer development by degrading E2F1 and c-Myc via circadian gene upregulation. Genes Cells 2024; 29:1012-1025. [PMID: 39357875 DOI: 10.1111/gtc.13161] [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: 07/13/2024] [Revised: 08/20/2024] [Accepted: 08/30/2024] [Indexed: 10/04/2024]
Abstract
Regular exercise is believed to suppress cancer progression. However, the precise molecular mechanisms by which exercise prevents cancer development remain unclear. In this study, using a steatosis-associated liver cancer mouse model, we found that regular exercise at a speed of 18 m/min for 20 min daily suppressed liver cancer development. To explore the underlying mechanisms, we examined the gene expression profiles in the livers of the exercise and non-exercise groups. The expressions of circadian genes, such as Per1 and Cry2, were upregulated in the exercise group. As circadian rhythm disruption is known to cause various diseases, including cancer, improving circadian rhythm through exercise could contribute to cancer prevention. We further found that the expression of a series of E2F1 and c-Myc target genes that directly affect the proliferation of cancer cells was downregulated in the exercise group. However, the expression of E2F1 and c-Myc was transcriptionally unchanged but degraded at the post-translational level by exercise. Cry2, which is regulated by the Skp1-Cul1-FBXL3 (SCFFBXL3) ubiquitin ligase complex by binding to FBXL3, can form a complex with E2F1 and c-Myc, which we think is the mechanism to degrade them. Our study revealed a previously unknown mechanism by which exercise prevents cancer development.
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Affiliation(s)
- Vu Thuong Huyen
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Department of Pathophysiology, Graduate School of Medicine, Osaka City University, Osaka, Japan
- Department of Pediatrics, Hanoi Medical University, Hanoi, Vietnam
| | - Kanae Echizen
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ryota Yamagishi
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Miho Kumagai
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan
| | - Yoshiki Nonaka
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Department of Pathophysiology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tatsuya Ando
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan
| | - Megumu Yano
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Naoki Takada
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Department of Orthopedic Surgery, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan
| | - Masaki Takasugi
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Fumitaka Kamachi
- Department of Pathophysiology, Graduate School of Medicine, Osaka City University, Osaka, Japan
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan
| | - Naoko Ohtani
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Department of Pathophysiology, Graduate School of Medicine, Osaka City University, Osaka, Japan
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan
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Marcantei C, Couret A, King J, Mazeaud S, Armand A, Ennequin G. Effects of Exercise Training on Muscle Mass and Physical Function in Patients with Hepatocellular Carcinoma After Diagnosis: A Systematic Review. Dig Dis Sci 2024; 69:2667-2680. [PMID: 38662157 DOI: 10.1007/s10620-024-08441-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 04/09/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND AND AIMS Decreased muscle mass and physical function are common complications in hepatocellular carcinoma (HCC) patients who are associated with increased morbidity and mortality. Thus, there have been targeted efforts to prevent and/or improve both by enrolling these patients in exercise training programs. We performed a systematic review to evaluate the effects of exercise training on muscle mass and physical function in people with HCC after diagnosis. METHODS A systematic literature search was conducted using the Medline, Base, PubMed, Cochrane and Scopus, and trial registries, through April 2023 for studies that assessed the effects of an exercise training program in adults with HCC. The primary outcomes were muscle mass and physical function. To assess the risk of bias, we used the Quality Assessment Tool for Quantitative Studies from the Effective Public Health Practice Project. RESULTS Eight studies met inclusion criteria, comprising a total of 809 participants. Interventions included aerobic exercise training, resistance exercise training, balance and flexibility training, or home-based exercise training. Four studies showed statistically significant improvements in at least one muscular outcome. Three studies showed a maintenance of muscular outcomes, and one study showed a decrease in muscle mass. Four articles showed statistically improvements in at least one physical fitness variable, and two showed a maintenance of physical function variable. CONCLUSION Together, the results suggest that patients may benefit from physical exercise training after treatment to improve muscle mass and physical function.
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Affiliation(s)
- Camille Marcantei
- Laboratory of the Metabolic Adaptations to Exercise Training Under Physiological and Pathological Conditions (AME2P), Clermont Auvergne University, CRNH Auvergne, Campus Universitaire Des Cézeaux, 3 Rue de La Chébarde, 63178, Clermont-Ferrand, AUBIERE Cedex, France.
| | - Alexis Couret
- Laboratory of the Metabolic Adaptations to Exercise Training Under Physiological and Pathological Conditions (AME2P), Clermont Auvergne University, CRNH Auvergne, Campus Universitaire Des Cézeaux, 3 Rue de La Chébarde, 63178, Clermont-Ferrand, AUBIERE Cedex, France
- Department of Digestive and Hepatobiliary Medecine, CHU, Clermont-Ferrand, France
- UMR 6602 CNRS-Sigma, Université Clermont Auvergne, Clermont-Ferrand, France
| | - James King
- National Centre for Sport and Exercise Training Medicine, School of Sport, Exercise Training and Health Sciences, Loughborough University, Loughborough, UK
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester, UK
| | - Simon Mazeaud
- Laboratory of the Metabolic Adaptations to Exercise Training Under Physiological and Pathological Conditions (AME2P), Clermont Auvergne University, CRNH Auvergne, Campus Universitaire Des Cézeaux, 3 Rue de La Chébarde, 63178, Clermont-Ferrand, AUBIERE Cedex, France
| | - Abergel Armand
- Department of Digestive and Hepatobiliary Medecine, CHU, Clermont-Ferrand, France
- UMR 6602 CNRS-Sigma, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Gaël Ennequin
- Laboratory of the Metabolic Adaptations to Exercise Training Under Physiological and Pathological Conditions (AME2P), Clermont Auvergne University, CRNH Auvergne, Campus Universitaire Des Cézeaux, 3 Rue de La Chébarde, 63178, Clermont-Ferrand, AUBIERE Cedex, France
- International Research Chair "Health in Motion", University Clermont Auvergne Foundation, Clermont-Ferrand, France
- Nutrition and Cancer Research Network (NACRe Network), Jouy-en-Josas, France
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Li M. Association of physical activity with MAFLD/MASLD and LF among adults in NHANES, 2017-2020. Wien Klin Wochenschr 2024; 136:258-266. [PMID: 38170220 DOI: 10.1007/s00508-023-02314-0] [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: 08/14/2023] [Accepted: 11/24/2023] [Indexed: 01/05/2024]
Abstract
OBJECTIVES To investigate the correlations between physical activity (PA) and metabolic associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) within a substantial population-based survey, and to examine the association between PA and liver fibrosis (LF). METHODS Data from the 2017-2020 NHANES cycle were utilized in this study. PA was divided into four types: leisure-time PA (LTPA), transportation-related PA (TPA), occupational PA (OPA) and total time PA (total PA, which is composed of OPA, TPA and LTPA). Weighted logistic regression models were performed to analyze the associations between PA and MAFLD/MASLD and LF. Mediation analysis was used to explore whether LTPA completely mediated the statistically significant relationship between total PA and MAFLD/MASLD or LF. RESULTS The study encompassed a sample size of 5897 participants aged 20 years and above, among the total participants, 2568 individuals with MAFLD and 2588 individuals with MASLD. There was no statistically significant correlation observed between OPA/TPA and MAFLD/MASLD and LF; however, active LTPA demonstrated an inverse association with MAFLD/MASLD (OR: 0.548; 95% CI: 0.458, 0.656/OR: 0.543; 95% CI: 0.453, 0.650), as well as a negative correlation with significant/advanced LF (OR: 0.457; 95% CI: 0.334,0.625/OR: 0.427; 95% CI: 0.295,0.619). There was also a significant inverse association between total PA and MAFLD/MASLD or LF, but this association was carried by the difference in LTPA. CONCLUSION Participation in active LTPA is associated with a reduced likelihood of MAFLD/MASLD and LF, while neither OPA nor TPA can replace these effects of LTPA.
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Affiliation(s)
- Minhua Li
- Zhujiang Hospital of Southern Medical University, 510150, Guangzhou, Guangdong, China.
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Chen H, Zhou H, Wu B, Lu H, Zhang J, Zhang Y, Gu Y, Zhou G, Xiang J, Yang J. Physical activity and exercise in liver cancer. LIVER RESEARCH 2024; 8:22-33. [PMID: 39959031 PMCID: PMC11771262 DOI: 10.1016/j.livres.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/04/2024] [Accepted: 03/04/2024] [Indexed: 02/18/2025]
Abstract
Sarcopenia and physical deconditioning are common complications in patients with liver cancer, which are frequently caused by insufficient physical activity and poor nutritional status, resulting in physical frailty and a significant impact on the patient's physical fitness. Notably, sarcopenia, frailty, and poor cardiopulmonary endurance have all been linked to higher mortality rates among patients with liver cancer. Exercise intervention significantly improves various health parameters in liver cancer patients, including metabolic syndrome, muscle wasting, cardiorespiratory endurance, health-related quality of life, and reduction in hepatic venous pressure gradient. However, the link between physical exercise and liver cancer is commonly overlooked. In this article, we will examine the impact of exercise on liver cancer and present the most recent evidence on the best types of exercise for various stages of liver cancer. This article also summarizes and discusses the molecular mechanisms that control metabolism and systemic immune function in tumors. In brief, physical exercise should be considered an important intervention in the prevention and treatment of liver cancer and its complications.
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Affiliation(s)
- Haiyan Chen
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Huimin Zhou
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Bo Wu
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Hanxiao Lu
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
- School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Jie Zhang
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Yan Zhang
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Yuanlong Gu
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Guangwen Zhou
- Department of General Surgery, Shanghai Sixth People's Hospital, Shanghai, China
| | - Jie Xiang
- Department of Endocrinology, Wuxi Mingci Cardiovascular Hospital, Wuxi, Jiangsu, China
| | - Jun Yang
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Jiangsu, China
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Spanoudaki M, Giaginis C, Karafyllaki D, Papadopoulos K, Solovos E, Antasouras G, Sfikas G, Papadopoulos AN, Papadopoulou SK. Exercise as a Promising Agent against Cancer: Evaluating Its Anti-Cancer Molecular Mechanisms. Cancers (Basel) 2023; 15:5135. [PMID: 37958310 PMCID: PMC10648074 DOI: 10.3390/cancers15215135] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/13/2023] [Accepted: 10/24/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Cancer cases are continuously increasing, while the prevalence rates of physical inactivity are also continuously increasing. Physical inactivity is a causative factor in non-communicable diseases, including cancer. However, the potential beneficial effects of exercise on cancer treatment have not received much attention so far. The aim of this study was to highlight the relationship between cancer and exercise on a molecular basis. METHODS Comprehensive and in-depth research was conducted in the most accurate scientific databases by using relevant and effective keywords. RESULTS The mechanisms by which exercise may reduce cancer risk and/or progression may include the metabolic profile of hormones, systemic inflammation reduction, insulin sensitivity increase, antioxidant capacity augmentation, the boost to the immune system, and the direct effect on the tumor. There is currently substantial evidence that the effect of exercise may predict a stronger association with cancer and could supplementarily be embedded in cancer clinical practice to improve disease progression and prognosis. CONCLUSION The field of this study requires interconnecting the overall knowledge of exercise physiology with cancer biology and cancer clinical oncology to provide the basis for personalized targeting strategies that can be merged with training as a component of a holistic co-treatment approach to optimize cancer healthcare.
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Affiliation(s)
- Maria Spanoudaki
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece; (M.S.); (A.N.P.); (S.K.P.)
- 424 General Military Hospital of Thessaloniki, 54621 Thessaloniki, Greece; (K.P.); (G.S.)
| | - Constantinos Giaginis
- Department of Food Science and Nutrition, School of Environment, University of Aegean, 81400 Lemnos, Greece;
| | - Dimitra Karafyllaki
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42132 Trikala, Greece;
| | | | - Evangelos Solovos
- 424 General Military Hospital of Thessaloniki, 54621 Thessaloniki, Greece; (K.P.); (G.S.)
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42132 Trikala, Greece;
| | - Georgios Antasouras
- Department of Food Science and Nutrition, School of Environment, University of Aegean, 81400 Lemnos, Greece;
| | - Georgios Sfikas
- 424 General Military Hospital of Thessaloniki, 54621 Thessaloniki, Greece; (K.P.); (G.S.)
| | - Athanasios N. Papadopoulos
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece; (M.S.); (A.N.P.); (S.K.P.)
| | - Sousana K. Papadopoulou
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece; (M.S.); (A.N.P.); (S.K.P.)
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DiJoseph K, Thorp A, Harrington A, Schmitz KH, Chinchilli VM, Stine JG. Physical Activity and Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Dig Dis Sci 2023; 68:1051-1059. [PMID: 35767138 DOI: 10.1007/s10620-022-07601-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/15/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Physical activity offers promise to protect against multiple non-hepatic primary cancers. We performed a systematic review to quantify the association between physical activity and hepatocellular carcinoma (HCC) risk. METHODS We searched the Cochrane Library, Embase, Medline and trial registries through December 2020 for studies that measured physical activity levels in adults at risk for HCC. The primary outcome was HCC. Subgroup analysis was performed limiting to vigorous physical activity. Proportions and random-effects odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS Seven studies met inclusion criteria, comprising 777,662 subjects (median age 55 years; 55% female). Greater amounts of physical activity were associated with less HCC (OR 0.65, 95% CI 0.45-0.95, p = 0.03) compared to lower amounts. Vigorous physical activity was associated with even less HCC (OR 0.62, 95% CI 0.49-0.79, p < 0.01). CONCLUSIONS This meta-analysis demonstrates that greater amounts of physical activity are associated with lower odds of HCC. These results support the use of regular physical activity as an effective way to prevent HCC and provide helpful data to support a for future exercise-based interventional study to better define the optimal exercise prescription for patients at risk for primary liver cancer.
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Affiliation(s)
- Kara DiJoseph
- Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Audrey Thorp
- Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Alex Harrington
- College of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Kathryn H Schmitz
- Department of Public Health Sciences, The Pennsylvania State University- College of Medicine, Hershey, PA, USA
- Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA
- Department of Kinesiology, The Pennsylvania State University- College of Health and Human Development, University Park, PA, USA
- Department of Physical Medicine & Rehabilitation, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Vernon M Chinchilli
- Department of Public Health Sciences, The Pennsylvania State University- College of Medicine, Hershey, PA, USA
| | - Jonathan G Stine
- Department of Public Health Sciences, The Pennsylvania State University- College of Medicine, Hershey, PA, USA.
- Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA.
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA.
- Liver Center, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA.
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Cernea S, Onișor D. Screening and interventions to prevent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:286-309. [PMID: 36687124 PMCID: PMC9846941 DOI: 10.3748/wjg.v29.i2.286] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/06/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Liver cancer is the sixth most commonly diagnosed cancer worldwide, with hepatocellular carcinoma (HCC) comprising most cases. Besides hepatitis B and C viral infections, heavy alcohol use, and nonalcoholic steatohepatitis (NASH)-associated advanced fibrosis/cirrhosis, several other risk factors for HCC have been identified (i.e. old age, obesity, insulin resistance, type 2 diabetes). These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection. HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease (NAFLD) patients, and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment. Patients with NASH-cirrhosis should undergo systematic HCC surveillance, while this might be considered in patients with advanced fibrosis based on individual risk assessment. In this context, interventions that potentially prevent NAFLD/ NASH-associated HCC are needed. This paper provided an overview of evidence related to lifestyle changes (i.e. weight loss, physical exercise, adherence to healthy dietary patterns, intake of certain dietary components, etc.) and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms. However, well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.
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Affiliation(s)
- Simona Cernea
- Department M3/Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureş 540139, Romania
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş 540136, Romania
| | - Danusia Onișor
- Department ME2/Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş 540139, Romania
- Gastroenterology Department, Mureș County Clinical Hospital, Târgu Mureș 540072, Romania
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Yeo SM, Oh JH, Yu HJ, Sinn DH, Hwang JH. The effect of mHealth-based exercise on Insulin Sensitivity for patients with Hepatocellular carcinoma and insulin resistance (mISH): protocol of a randomized controlled trial. Trials 2022; 23:930. [DOI: 10.1186/s13063-022-06858-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 10/20/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The importance of insulin resistance is gaining increasing attention as it plays an important role in carcinogenesis in hepatocellular carcinoma (HCC). Although exercise is the most important intervention for lowering insulin resistance, it is not easy for HCC patients to maintain high compliance and do appropriate exercise. Mobile health (mHealth) with wearable devices can be the solution to carry out an adjusted and supervised exercise that can normalize insulin resistance in patients with HCC. We developed an HCC-specific application equipped with patient-centered exercise. In this paper, we present a randomized controlled trial protocol comparing an intervention group with a control group to determine whether mHealth-based exercise is effective in normalizing insulin sensitivity in HCC patients with insulin resistance after anticancer treatment.
Methods
An assessor unblinded open label randomized controlled trial (RCT) will be conducted for 80 participants with treatment-naïve or recurrent HCC who have received treatment and achieved complete response at the time of screening. They will be randomly assigned (1:1) to one of two groups: an intervention group (n = 40) and a control group (n = 40). The intervention group will carry out mHealth-based exercise for 6 months from baseline, whereas the control group will receive the usual follow-up care for the first 3 months and mHealth-based exercise for the next 3 months. Both groups will be assessed at baseline, 3 months, and 6 months from baseline. The primary outcome is the normalized rate of insulin resistance in each group at 3 months. Insulin resistance is estimated by calculating homeostatic model assessment for insulin resistance (HOMA-IR). The secondary outcomes are body composition, physical fitness level, physical activity, and quality of life at 3 months.
Discussion
This study is the first RCT to investigate the effect of mHealth-based home exercise with a wrist-wearable device on insulin sensitivity, physical fitness, and quality of life for HCC patients with insulin resistance. The result of this RCT will confirm not only safety and functional improvement but also biological effect when exercising using mHealth in HCC patients.
Trial registration
ClinicalTrials.gov NCT04649671. Registered on 2 December 2020. The World Health Organization Trial Registration Data Set is not registered.
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Torregrosa C, Chorin F, Beltran EEM, Neuzillet C, Cardot-Ruffino V. Physical Activity as the Best Supportive Care in Cancer: The Clinician's and the Researcher's Perspectives. Cancers (Basel) 2022; 14:5402. [PMID: 36358820 PMCID: PMC9655932 DOI: 10.3390/cancers14215402] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/27/2022] [Accepted: 10/31/2022] [Indexed: 08/11/2023] Open
Abstract
Multidisciplinary supportive care, integrating the dimensions of exercise alongside oncological treatments, is now regarded as a new paradigm to improve patient survival and quality of life. Its impact is important on the factors that control tumor development, such as the immune system, inflammation, tissue perfusion, hypoxia, insulin resistance, metabolism, glucocorticoid levels, and cachexia. An increasing amount of research has been published in the last years on the effects of physical activity within the framework of oncology, marking the appearance of a new medical field, commonly known as "exercise oncology". This emerging research field is trying to determine the biological mechanisms by which, aerobic exercise affects the incidence of cancer, the progression and/or the appearance of metastases. We propose an overview of the current state of the art physical exercise interventions in the management of cancer patients, including a pragmatic perspective with tips for routine practice. We then develop the emerging mechanistic views about physical exercise and their potential clinical applications. Moving toward a more personalized, integrated, patient-centered, and multidisciplinary management, by trying to understand the different interactions between the cancer and the host, as well as the impact of the disease and the treatments on the different organs, this seems to be the most promising method to improve the care of cancer patients.
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Affiliation(s)
- Cécile Torregrosa
- Oncologie Digestive, Département d’Oncologie Médicale Institut Curie, Université Versailles Saint-Quentin—Université Paris Saclay, 35, rue Dailly, 92210 Saint-Cloud, France
- Département de Chirurgie Digestive et Oncologique, Hôpital Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, 9 avenue Charles de Gaulle, 92100 Boulogne Billancourt, France
| | - Frédéric Chorin
- Laboratoire Motricité Humaine, Expertise, Sport, Santé (LAMHESS), HEALTHY Graduate School, Université Côte d’Azur, 06205 Nice, France
- Clinique Gériatrique du Cerveau et du Mouvement, Centre Hospitalier Universitaire de Nice, Université Côte d’Azur, 06205 Nice, France
| | - Eva Ester Molina Beltran
- Oncologie Digestive, Département d’Oncologie Médicale Institut Curie, Université Versailles Saint-Quentin—Université Paris Saclay, 35, rue Dailly, 92210 Saint-Cloud, France
| | - Cindy Neuzillet
- Oncologie Digestive, Département d’Oncologie Médicale Institut Curie, Université Versailles Saint-Quentin—Université Paris Saclay, 35, rue Dailly, 92210 Saint-Cloud, France
- GERCOR, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France
| | - Victoire Cardot-Ruffino
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
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12
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Seet-Lee C, Yee J, Morahan H, Ross LS, Edwards KM. The effect of aerobic exercise on tumour blood delivery: a systematic review and meta-analysis. Support Care Cancer 2022; 30:8637-8653. [PMID: 35650456 PMCID: PMC9633495 DOI: 10.1007/s00520-022-07132-0] [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] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/09/2022] [Indexed: 01/05/2023]
Abstract
PURPOSE Tumour blood vessels are structurally and functionally abnormal, resulting in areas of hypoxia and heterogeneous blood supply. Aerobic exercise may modulate tumour blood flow and normalise the tumour microenvironment to improve chemotherapy delivery. This systematic review and meta-analysis aimed to evaluate the effect of the aerobic exercise mode on tumour hypoxia, vascularisation and blood flow. METHODS Four online databases were searched. Preclinical and clinical randomised controlled trials examining the effects of aerobic exercise training on hypoxia, vascularisation or blood flow in solid tumours were included. The risk of bias was assessed and a meta-analysis performed. RESULTS Seventeen preclinical studies and one clinical study met criteria. Eleven studies assessed hypoxia, 15 studies assessed vascularisation and seven evaluated blood flow. There was large variability in measurement methods, tumour types and exercise program designs. The overall risk of bias was unclear in clinical and preclinical studies, owing to poor reporting. There was no significant effect of aerobic exercise on hypoxia (SMD = -0.17; 95% CI = -0.62, 0.28; I2 = 60%), vascularisation (SMD = 0.07; 95% CI = -0.40, 0.55; I2 = 71%) or blood flow (SMD = 0.01; 95% CI = -0.59, 0.61; I2 = 63%). CONCLUSION There is heterogeneity in methodology, resulting in evidence that is inconsistent and inconclusive for the effects of aerobic exercise on hypoxia, vascularisation and blood flow. Most evidence of aerobic exercise effects on tumour blood flow is in animal models, with very limited evidence in humans.
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Affiliation(s)
- Catherine Seet-Lee
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, Australia
| | - Jasmine Yee
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, Australia
- Centre for Medical Psychology & Evidence-Based Decision-Making, School of Psychology, The University of Sydney, Camperdown, Australia
| | - Heidi Morahan
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, Australia
| | - Lois S Ross
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, Australia
- Department for Health, University of Bath, Bath, UK
| | - Kate M Edwards
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia.
- Charles Perkins Centre, University of Sydney, Camperdown, Australia.
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13
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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14
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Jee H, Park E, Hur K, Kang M, Kim Y. High-Intensity Aerobic Exercise Suppresses Cancer Growth by Regulating Skeletal Muscle-Derived Oncogenes and Tumor Suppressors. Front Mol Biosci 2022; 9:818470. [PMID: 35801156 PMCID: PMC9254717 DOI: 10.3389/fmolb.2022.818470] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
High-intensity aerobic exercise (90% of the maximal heart rate) can effectively suppress cancer cell proliferation in vivo. However, the molecular effects of exercise and its relevance to cancer prevention remain uninvestigated. In this study, mice with colorectal cancer were subjected to high-intensity aerobic exercise, and mRNA-seq analysis was performed on the heart, lungs, and skeletal muscle tissues to analyze the genome-wide molecular effects of exercise. The skeletal muscle-derived genes with exercise-dependent differential expression were further evaluated for their effects on colorectal cancer cell viability. Compared to the results obtained for the control groups (healthy and cancer with no exercise), the regular and high-intensity aerobic physical activity in the mice produced positive results in comprehensive parameters (i.e., food intake, weight gain, and survival rate). A heatmap of differentially expressed genes revealed markedly different gene expression patterns among the groups. RNA-seq analysis of 23,282 genes expressed in the skeletal muscle yielded several anticancer effector genes (e.g., Trim63, Fos, Col1a1, and Six2). Knockdown and overexpression of selected anticancer genes repressed CT26 murine colorectal carcinoma cell proliferation by 20% (p < 0.05). Our findings, based on the aerobic exercise cancer mouse model, suggest that high-intensity aerobic exercise results in a comprehensive change in the expression patterns of genes, particularly those that can affect cancer cell viability. Such an approach may identify key exercise-regulated genes that can help the body combat cancer.
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Affiliation(s)
- Hyunseok Jee
- School of Kinesiology, Yeungnam University, Gyeongsan, South Korea
- College of Life Science and Nano Technology, Hannam University, Daejeon, South Korea
| | - Eunmi Park
- College of Life Science and Nano Technology, Hannam University, Daejeon, South Korea
| | - Kyunghoon Hur
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Minjeong Kang
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Yoosik Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- KAIST Institute for Health Science and Technology (KIHST), KAIST, Daejeon, South Korea
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15
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Nardo WD, Miotto PM, Bayliss J, Nie S, Keenan SN, Montgomery MK, Watt MJ. Proteomic analysis reveals exercise training induced remodelling of hepatokine secretion and uncovers syndecan-4 as a regulator of hepatic lipid metabolism. Mol Metab 2022; 60:101491. [PMID: 35381388 PMCID: PMC9034320 DOI: 10.1016/j.molmet.2022.101491] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 11/04/2022] Open
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is linked to impaired lipid metabolism and systemic insulin resistance, which is partly mediated by altered secretion of liver proteins known as hepatokines. Regular physical activity can resolve NAFLD and improve its metabolic comorbidities, however, the effects of exercise training on hepatokine secretion and the metabolic impact of exercise-regulated hepatokines in NAFLD remain unresolved. Herein, we examined the effect of endurance exercise training on hepatocyte secreted proteins with the aim of identifying proteins that regulate metabolism and reduce NAFLD severity. Methods C57BL/6 mice were fed a high-fat diet for six weeks to induce NAFLD. Mice were exercise trained for a further six weeks, while the control group remained sedentary. Hepatocytes were isolated two days after the last exercise bout, and intracellular and secreted proteins were detected using label-free mass spectrometry. Hepatocyte secreted factors were applied to skeletal muscle and liver ex vivo and insulin action and fatty acid metabolism were assessed. Syndecan-4 (SDC4), identified as an exercise-responsive hepatokine, was overexpressed in the livers of mice using adeno-associated virus. Whole-body energy homeostasis was assessed by indirect calorimetry and skeletal muscle and liver metabolism was assessed using radiometric techniques. Results Proteomics analysis detected 2657 intracellular and 1593 secreted proteins from mouse hepatocytes. Exercise training remodelled the hepatocyte proteome, with differences in 137 intracellular and 35 secreted proteins. Bioinformatic analysis of hepatocyte secreted proteins revealed enrichment of tumour suppressive proteins and proteins involved in lipid metabolism and mitochondrial function, and suppression of oncogenes and regulators of oxidative stress. Hepatocyte secreted factors from exercise trained mice improved insulin action in skeletal muscle and increased hepatic fatty acid oxidation. Hepatocyte-specific overexpression of SDC4 reduced hepatic steatosis, which was associated with reduced hepatic fatty acid uptake, and blunted pro-inflammatory and pro-fibrotic gene expression. Treating hepatocytes with recombinant ectodomain of SDC4 (secreted form) recapitulated these effects with reduced fatty acid uptake, lipid storage and lipid droplet accumulation. Conclusions Remodelling of hepatokine secretion is an adaptation to regular exercise training that induces changes in metabolism in the liver and skeletal muscle. SDC4 is a novel exercise-responsive hepatokine that decreases fatty acid uptake and reduces steatosis in the liver. By understanding the proteomic changes in hepatocytes with exercise, these findings have potential for the discovery of new therapeutic targets for NAFLD.
Exercise training remodels hepatokine secretion. Exercise regulated secreted factors improve insulin action in skeletal muscle. Syndecan-4 (SDC4) is a novel exercise-induced hepatokine. SDC4 reduces hepatic fatty acid uptake and hepatic steatosis.
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16
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Zhong D, Li Y, Huang Y, Hong X, Li J, Jin R. Molecular Mechanisms of Exercise on Cancer: A Bibliometrics Study and Visualization Analysis via CiteSpace. Front Mol Biosci 2022; 8:797902. [PMID: 35096970 PMCID: PMC8794585 DOI: 10.3389/fmolb.2021.797902] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/21/2021] [Indexed: 12/24/2022] Open
Abstract
Objective: To analyze the research hot spots and frontiers of molecular mechanisms of exercise on cancer via CiteSpace. Method: Related publications in the Web of Science Core Collection Science Citation Index Expanded were retrieved from inception to November 27th, 2021. Then we used CiteSpace to generate network maps and identify top authors, institutions, countries, keywords, co-cited authors, journals, references and research trends. Results: A total of 1,130 related publications were retrieved. The most productive author and journal were Lee W Jones and PLOS ONE. Hanahan D and Warburg O were the most cited authors. Fudan University and Shanghai Jiao Tong University were the leading institutions, while China was the leading country. Top-cited authors and references generally focused on the epidemiology and hallmarks of cancer. Top five keywords with both high frequency and high betweenness centrality were breast cancer, aerobic glycolysis, oxidative stress, gene expression, skeletal muscle. Keyword “warburg effect” ranked first with the highest citation burst, while “inflammation”, “hepatocellular carcinoma”, “epithelial mesenchymal transition”, and “adipose tissue” were emerging research foci. Conclusion: This study analyzed the research hot spots and frontiers of molecular mechanisms of exercise on cancer via CiteSpace. Based on the results, altered metabolism (aerobic glycolysis, insulin resistance, myokines), oxidative stress, gene expression and apoptosis were hot-research mechanisms of exercise on cancer. Emerging research foci of mechanisms were generally around inflammation, epithelial mesenchymal transition and adipokines. In addition, future studies could carry in-depth research of interactions between different mechanisms and try to elucidate the recommended doses and intensities of exercise for cancer, especially in breast, colorectal, prostate cancer and hepatocellular carcinoma.
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Affiliation(s)
- Dongling Zhong
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuxi Li
- School of Acupuncture Moxibustion and Tuina, The Third Affiliated Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yijie Huang
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xiaojuan Hong
- School of Acupuncture Moxibustion and Tuina, The Third Affiliated Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Xiaojuan Hong, ; Rongjiang Jin, ; Juan Li,
| | - Juan Li
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Xiaojuan Hong, ; Rongjiang Jin, ; Juan Li,
| | - Rongjiang Jin
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Xiaojuan Hong, ; Rongjiang Jin, ; Juan Li,
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17
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Zelber-Sagi S, Noureddin M, Shibolet O. Lifestyle and Hepatocellular Carcinoma What Is the Evidence and Prevention Recommendations. Cancers (Basel) 2021; 14:cancers14010103. [PMID: 35008267 PMCID: PMC8750465 DOI: 10.3390/cancers14010103] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The increasing public health burden of Hepatocellular carcinoma (HCC) emphasizes the importance of defining important modifiable risk factors. In the following review, we will discuss the evidence for the relation of major lifestyle risk factors, mostly from large population-based studies. Generally, it is has been shown that healthy lifestyle habits, including minimizing obesity, eating a healthy diet, avoidance of smoking and alcohol, and increasing physical activity, have the potential to prevent HCC. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, vegetables and fiber, are inversely associated with HCC, while red meat, saturated fat, cholesterol and sugar are related to increased risk. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. Smoking and alcohol can lead to liver fibrosis and liver cancer and jointly lead to an even greater risk. Abstract The increasing burden of hepatocellular carcinoma (HCC) emphasizes the unmet need for primary prevention. Lifestyle measures appear to be important modifiable risk factors for HCC regardless of its etiology. Lifestyle patterns, as a whole and each component separately, are related to HCC risk. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, are inversely associated with HCC, while red meat, saturated fat, and cholesterol are related to increased risk. Sugar consumption is associated with HCC risk, while fiber and vegetable intake is protective. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. However, the duration, mode and intensity of physical activity needed are yet to be determined. There is evidence that smoking can lead to liver fibrosis and liver cancer and has a synergistic effect with alcohol drinking. On the other hand, an excessive amount of alcohol by itself has been associated with increased risk of HCC directly (carcinogenic effect) or indirectly (liver fibrosis and cirrhosis progression. Large-scale intervention studies testing the effect of comprehensive lifestyle interventions on HCC prevention among diverse cohorts of liver disease patients are greatly warranted.
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Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Correspondence: ; Tel.: +972-54-4634440; Fax: +972-3-5446086
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Oren Shibolet
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6697801, Israel
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18
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Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention. J Hepatol 2021; 75:1217-1227. [PMID: 34339764 DOI: 10.1016/j.jhep.2021.07.025] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.
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19
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Bae JH, Seo DY, Lee SH, Shin C, Jamrasi P, Han J, Song W. Effects of exercise on AKT/PGC1-α/FOXO3a pathway and muscle atrophy in cisplatin-administered rat skeletal muscle. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2021; 25:585-592. [PMID: 34697269 PMCID: PMC8552830 DOI: 10.4196/kjpp.2021.25.6.585] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/19/2021] [Accepted: 08/26/2021] [Indexed: 01/06/2023]
Abstract
Cisplatin has been reported to cause side effects such as muscle wasting in
humans and rodents. The physiological mechanisms involved in preventing muscle
wasting, such as the regulation of AKT, PGC1-α, and autophagy-related
factor FOXO3a by MuRF 1 and Atrogin-1, remain unclear following different types
of exercise and in various skeletal muscle types. Eight-week-old male Wistar
rats (n = 34) were assigned to one of four groups: control (CON, n = 6),
cisplatin injection (1 mg/kg) without exercise (CC, n = 8), cisplatin (1 mg/kg)
+ resistance exercise (CRE, n = 9) group, and cisplatin (1 mg/kg) + aerobic
exercise (CAE, n = 11). The CRE group performed progressive ladder exercise
(starting with 10% of body weight on a 1-m ladder with 2-cm-interval grids, at
85°) for 8 weeks. The CAE group exercised by treadmill running (20 m/min
for 60 min daily, 4 times/week) for 8 weeks. Compared with the CC group, the
levels of the autophagy-related factors BNIP3, Beclin 1, LC3-II/I ratio, p62,
and FOXO3a in the gastrocnemius and soleus muscles were significantly decreased
in the CRE and CAE groups. The CRE and CAE groups further showed significantly
decreased MuRF 1 and Atrogin-1 levels and increased phosphorylation of AKT,
FOXO3a, and PGC1-α. These results suggest that both ladder and aerobic
exercise directly affected muscle wasting by modulating the
AKT/PGC1-α/FOXO3a signaling pathways regardless of the skeletal muscle
type.
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Affiliation(s)
- Jun Hyun Bae
- Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University, Seoul 08826, Korea
| | - Dae Yun Seo
- National ResearchLaboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University
| | - Sang Ho Lee
- Department of Taekwondo, Dong-A University, Busan 49315, Korea
| | - Chaeyoung Shin
- Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University, Seoul 08826, Korea
| | - Parivash Jamrasi
- Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University, Seoul 08826, Korea
| | - Jin Han
- National ResearchLaboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University
| | - Wook Song
- Health and Exercise Science Laboratory, Institute of Sports Science, Seoul National University, Seoul 08826, Korea.,Institute of Aging, Seoul National University, Seoul 08826, Korea
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20
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Kronenfeld JP, Goel N. An Analysis of Individual and Contextual-Level Disparities in Screening, Treatment, and Outcomes for Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:1209-1219. [PMID: 34611524 PMCID: PMC8487287 DOI: 10.2147/jhc.s284430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/02/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and affects patients of all genders, races, ethnicities, and socioeconomic status. While the causes of HCC are numerous, the primary etiology is cirrhosis from alcohol and non-alcoholic fatty liver disease in the United States and from infectious agents such as Hepatitis B and Hepatitis C in the developing world. In patients at-risk for developing HCC, screening is recommended with ultrasound imaging and alpha fetoprotein laboratory tests. In socioeconomically vulnerable patients, however, individual-level barriers (eg, insurance status) and contextual-level disparities (eg, health facilities) may not be readily available, thus limiting screening. Additional challenges faced by racial/ethnic minorities can further challenge the spectrum of HCC care and lead to inadequate screening, delayed diagnosis, and unequal access to treatment. Efforts to improve these multilevel factors that lead to screening and treatment disparities are critical to overcoming challenges. Providing health insurance to those without access, improving societal challenges that confine patients to a lower socioeconomic status, and reducing challenges to seeking healthcare can decrease the morbidity and mortality of these patients. Additionally, engaging with communities and allowing them to collaborate in their own healthcare can also help to attenuate these inequities. Through collaborative multidisciplinary change, we can make progress in tackling disparities in vulnerable populations to achieve health equity
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Affiliation(s)
- Joshua P Kronenfeld
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Neha Goel
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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21
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Semmler G, Datz C, Reiberger T, Trauner M. Diet and exercise in NAFLD/NASH: Beyond the obvious. Liver Int 2021; 41:2249-2268. [PMID: 34328248 PMCID: PMC9292198 DOI: 10.1111/liv.15024] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/06/2021] [Accepted: 07/10/2021] [Indexed: 12/12/2022]
Abstract
Lifestyle represents the most relevant factor for non-alcoholic fatty liver disease (NAFLD) as the hepatic manifestation of the metabolic syndrome. Although a tremendous body of clinical and preclinical data on the effectiveness of dietary and lifestyle interventions exist, the complexity of this topic makes firm and evidence-based clinical recommendations for nutrition and exercise in NAFLD difficult. The aim of this review is to guide readers through the labyrinth of recent scientific findings on diet and exercise in NAFLD and non-alcoholic steatohepatitis (NASH), summarizing "obvious" findings in a holistic manner and simultaneously highlighting stimulating aspects of clinical and translational research "beyond the obvious". Specifically, the importance of calorie restriction regardless of dietary composition and evidence from low-carbohydrate diets to target the incidence and severity of NAFLD are discussed. The aspect of ketogenesis-potentially achieved via intermittent calorie restriction-seems to be a central aspect of these diets warranting further investigation. Interactions of diet and exercise with the gut microbiota and the individual genetic background need to be comprehensively understood in order to develop personalized dietary concepts and exercise strategies for patients with NAFLD/NASH.
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Affiliation(s)
- Georg Semmler
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Christian Datz
- Department of Internal MedicineGeneral Hospital OberndorfTeaching Hospital of the Paracelsus Medical University SalzburgSalzburgAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
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22
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Qiu J, Sato Y, Xu L, Miura T, Kohzuki M, Ito O. Chronic Exercise Protects against the Progression of Renal Cyst Growth and Dysfunction in Rats with Polycystic Kidney Disease. Med Sci Sports Exerc 2021; 53:2485-2494. [PMID: 34310502 PMCID: PMC8594502 DOI: 10.1249/mss.0000000000002737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Introduction Polycystic kidney disease (PKD) is a genetic disorder characterized by the progressive enlargement of renal epithelial cysts and renal dysfunction. Previous studies have reported the beneficial effects of chronic exercise on chronic kidney disease. However, the effects of chronic exercise have not been fully examined in PKD patients or models. The effects of chronic exercise on the progression of PKD were investigated in a polycystic kidney (PCK) rat model. Methods Six-week-old male PCK rats were divided into a sedentary group and an exercise group. The exercise group underwent forced treadmill exercise for 12 wk (28 m·min−1, 60 min·d−1, 5 d·wk−1). After 12 wk, renal function and histology were examined, and signaling cascades of PKD progression, including arginine vasopressin (AVP), were investigated. Results Chronic exercise reduced the excretion of urinary protein, liver-type fatty acid–binding protein, plasma creatinine, urea nitrogen, and increased plasma irisin and urinary AVP excretion. Chronic exercise also slowed renal cyst growth, glomerular damage, and interstitial fibrosis and led to reduced Ki-67 expression. Chronic exercise had no effect on cAMP content but decreased the renal expression of B-Raf and reduced the phosphorylation of extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), and S6. Conclusion Chronic exercise slows renal cyst growth and damage in PCK rats, despite increasing AVP, with the downregulation of the cAMP/B-Raf/ERK and mTOR/S6 pathways in the kidney of PCK rats.
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Affiliation(s)
- Jiahe Qiu
- Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine, Sendai, Japan Division of General Medicine and Rehabilitation, Tohoku Medical and Pharmaceutical University Faculty of Medicine, Sendai, Japan
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23
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Chun HS, Park S, Lee M, Cho Y, Kim HS, Choe AR, Kim HY, Yoo K, Kim TH. Association of Physical Activity with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B. Cancers (Basel) 2021; 13:cancers13143424. [PMID: 34298640 PMCID: PMC8306325 DOI: 10.3390/cancers13143424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/17/2021] [Accepted: 06/28/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Although viral replication in patients with a chronic hepatitis B (CHB) infection is effectively suppressed by potent antiviral therapy such as entecavir or tenofovir, the risk of hepatocellular carcinoma (HCC) development in CHB patients cannot be totally eliminated. Thus, control of modifiable risk factors for HCC development such as lifestyle modification is important to minimize the HCC risk. In this study, we analyzed a nationwide population-based cohort to evaluate whether there is a significant association between physical activity and development of HCC in CHB patients treated with entecavir or tenofovir. Results in this study suggest that physical activity was significantly associated with a lower risk of HCC development in CHB patients treated with potent antiviral therapy. Increasing physical activity can have beneficial outcomes on HCC development in CHB patients treated with entecavir or tenofovir. Abstract Background and Aims: In the general population, previous studies reported that physical activity was associated with risk of hepatocellular carcinoma (HCC) development. However, it is unclear whether physical activity is associated with risk of HCC development in patients with chronic hepatitis B (CHB). We aimed to elucidate the association between physical activity and risk of HCC development in CHB patients. Methods: This nationwide cohort study involved treatment-naive patients with CHB (n = 9727) who started treatment with entecavir or tenofovir and answered self-reported questionnaires between January 2012 and December 2017, using data from the Korean National Health Insurance Service database. The primary endpoint was development of HCC. Multivariable Cox regression and competing risk analyses were used. Results: During a median follow-up of 3.1 years, cumulative HCC incidence rates were 8.3%. There was an inverse association between physical activity and the risk of HCC (p < 0.001). Patients with 1000–1500 metabolic equivalent task (MET)-min/week, compared to those without physical activity, showed a significantly lower risk of HCC in both patients without cirrhosis (adjusted hazard ratio [aHR] 0.66, p = 0.02) and patients with cirrhosis (aHR 0.61, p = 0.02). In patients who were younger (<60), male, without diabetes, and with high BMI, amounts of physical activity of 1000–1500 MET-min/week showed an inverse association with the risk of HCC (aHR 0.65, 0.63, 0.65, and 0.64, respectively, all p < 0.05). Conclusion: Physical activity was significantly associated with a low risk of HCC in CHB patients treated with entecavir or tenofovir.
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Affiliation(s)
- Ho Soo Chun
- Ewha Womans University Medical Center, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul 07804, Korea; (H.S.C.); (A.R.C.); (H.Y.K.); (K.Y.)
| | - Sojeong Park
- Data Science Team, Hanmi Pharmaceutical Co., Ltd., Seoul 05545, Korea; (S.P.); (H.S.K.)
| | - Minjong Lee
- Ewha Womans University Medical Center, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul 07804, Korea; (H.S.C.); (A.R.C.); (H.Y.K.); (K.Y.)
- Correspondence: (M.L.); (T.H.K.); Tel.: +82-2-6986-1761 (M.L.); +82-2-6986-1621 (T.H.K.)
| | - Yuri Cho
- National Cancer Center, Center for Liver and Pancreatobiliary Cancer, Goyang 10408, Korea;
| | - Ha Sung Kim
- Data Science Team, Hanmi Pharmaceutical Co., Ltd., Seoul 05545, Korea; (S.P.); (H.S.K.)
| | - A Reum Choe
- Ewha Womans University Medical Center, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul 07804, Korea; (H.S.C.); (A.R.C.); (H.Y.K.); (K.Y.)
| | - Hwi Young Kim
- Ewha Womans University Medical Center, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul 07804, Korea; (H.S.C.); (A.R.C.); (H.Y.K.); (K.Y.)
| | - Kwon Yoo
- Ewha Womans University Medical Center, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul 07804, Korea; (H.S.C.); (A.R.C.); (H.Y.K.); (K.Y.)
| | - Tae Hun Kim
- Ewha Womans University Medical Center, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul 07804, Korea; (H.S.C.); (A.R.C.); (H.Y.K.); (K.Y.)
- Correspondence: (M.L.); (T.H.K.); Tel.: +82-2-6986-1761 (M.L.); +82-2-6986-1621 (T.H.K.)
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Gallage S, García-Beccaria M, Szydlowska M, Rahbari M, Mohr R, Tacke F, Heikenwalder M. The therapeutic landscape of hepatocellular carcinoma. MED 2021; 2:505-552. [PMID: 35590232 DOI: 10.1016/j.medj.2021.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/23/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
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25
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Geh D, Anstee QM, Reeves HL. NAFLD-Associated HCC: Progress and Opportunities. J Hepatocell Carcinoma 2021; 8:223-239. [PMID: 33854987 PMCID: PMC8041650 DOI: 10.2147/jhc.s272213] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.
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Affiliation(s)
- Daniel Geh
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
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26
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Melo L, Tilmant K, Hagar A, Klaunig JE. Effect of endurance exercise training on liver gene expression in male and female mice. Appl Physiol Nutr Metab 2020; 46:356-367. [PMID: 33052711 DOI: 10.1139/apnm-2020-0379] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic endurance exercise is a therapeutic strategy in the treatment of many chronic diseases in humans, including the prevention and treatment of metabolic diseases such as diabetes mellitus. Metabolic, cardiorespiratory, and endocrine pathways targeted by chronic endurance exercise have been identified. In the liver, however, the cellular and molecular pathways that are modified by exercise and have preventive or therapeutic relevance to metabolic disease need to be elucidated. The mouse model used in the current study allows for the quantification of a human-relevant exercise "dosage". In this study we show hepatic gene expression differences between sedentary female and sedentary male mice and that chronic exercise modifies the transcription of hepatic genes related to metabolic disease and steatosis in both male and female mice. Chronic exercise induces molecular pathways involved in glucose tolerance, glycolysis, and gluconeogenesis while producing a decrease in pathways related to insulin resistance, steatosis, fibrosis, and inflammation. Given these findings, this mouse exercise model has potential to dissect the cellular and molecular hepatic changes following chronic exercise with application to understanding the role that chronic exercise plays in preventing human diseases. Novelty: Exercise modifies the hepatic gene expression and hepatic pathways related to metabolic disease in male and female mice. Sex differences were seen in hepatic gene expression between sedentary and exercised mice. The mouse exercise model used in this study allows for application and evaluation of exercise effects in human disease.
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Affiliation(s)
- Luma Melo
- Laboratory of Investigative Toxicology and Pathology, Department of Environmental and Occupational Health, Indiana School of Public Health, Indiana University, Bloomington, IN 47405, USA
| | - Karen Tilmant
- Laboratory of Investigative Toxicology and Pathology, Department of Environmental and Occupational Health, Indiana School of Public Health, Indiana University, Bloomington, IN 47405, USA
| | - Amit Hagar
- History & Philosophy of Science & Medicine Department, Indiana University, Bloomington, IN 47405, USA.,Intelligent Systems Engineering Department, Indiana University, Bloomington, IN, USA
| | - James E Klaunig
- Laboratory of Investigative Toxicology and Pathology, Department of Environmental and Occupational Health, Indiana School of Public Health, Indiana University, Bloomington, IN 47405, USA
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27
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Yu CX, Chen YS, Ge ZJ, Zhang YH, Xu X, Tian T, Wen Y, Zhu J, Song C, Chen JG, Hu ZB. Dietary habits and risk of hepatocellular carcinoma among hepatitis B surface antigen carriers: A prospective cohort study in China. J Dig Dis 2020; 21:406-415. [PMID: 32407579 DOI: 10.1111/1751-2980.12878] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/29/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE In this prospective cohort study, we aimed to evaluate the association between dietary habits and the risk of developing hepatocellular carcinoma (HCC) in hepatitis B surface antigen (HBsAg)-positive carriers in Qidong, an hepatitis B virus (HBV)-epidemic area in China. METHODS A total of 3199 HBsAg carriers aged 30-70 years in a prospective cohort in Qidong, China from 2007 to 2011 were included in the study. At baseline, all participants self-reported their dietary habits in a questionnaire interview. A follow-up check-up was performed every 6 months to identify HCC cases until November 2017. Cox's regression analysis and an interaction analysis were performed to estimate the relative risks of HCC in terms of baseline diet. RESULTS Among 3199 HBsAg-positive participants, 270 developed HCC (143.86/100 000 person-years [PYs]). Compared with participants who rarely consume garlic, the risk of HCC in those who consumed it ≥ once per week decreased along with the increase in frequency (HR = 1.00, 0.90 and 0.62 in those who consumed it rarely vs those who consumed it 1-6 times per week and ≥ 7 times per week, respectively). This study found a synergistic effect between garlic and tea consumption on the risk of HCC (P = 0.039 for a multiplicative interaction). CONCLUSIONS HBsAg carriers should improve their diet. Regular consumption of garlic and tea drinking may reduce the HCC incidence in HBsAg carriers.
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Affiliation(s)
- Cheng Xiao Yu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yong Sheng Chen
- Qidong Liver Cancer Institute, Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong, Jiangsu Province, China
| | - Zi Jun Ge
- Department of Infection Management, Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu Province, China
| | - Yong Hui Zhang
- Qidong Liver Cancer Institute, Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong, Jiangsu Province, China
| | - Xin Xu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ting Tian
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yang Wen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Jian Zhu
- Qidong Liver Cancer Institute, Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong, Jiangsu Province, China
| | - Ci Song
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Jian Guo Chen
- Qidong Liver Cancer Institute, Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong, Jiangsu Province, China.,Affiliated Tumor Hospital/Institute, Nantong University, Nantong, Jiangsu Province, China
| | - Zhi Bin Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China
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28
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Guarino M, Kumar P, Felser A, Terracciano LM, Guixé-Muntet S, Humar B, Foti M, Nuoffer JM, St-Pierre MV, Dufour JF. Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice. Cancers (Basel) 2020; 12:E1407. [PMID: 32486073 PMCID: PMC7352494 DOI: 10.3390/cancers12061407] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/18/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) leads to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. For sedentary patients, lifestyle interventions combining exercise and dietary changes are a cornerstone of treatment. However, the benefit of exercise alone when dietary changes have failed is uncertain. We query whether exercise alone arrests the progression of NASH and tumorigenesis in a choline-deficient, high-fat diet (CD-HFD) murine model. Male C57Bl/6N mice received a control diet or CD-HFD for 12 weeks. CD-HFD mice were randomized further for 8 weeks of sedentariness (SED) or treadmill exercise (EXE). CD-HFD for 12 weeks produced NAFL. After 20 weeks, SED mice developed NASH and hepatic adenomas. Exercise attenuated the progression to NASH. EXE livers showed lower triglycerides and tumor necrosis factor-α expression, less fibrosis, less ballooning, and a lower NAFLD activity score than did SED livers. Plasma transaminases and triglycerides were lower. Exercise activated AMP-activated protein kinase (AMPK) with inhibition of mTORC1 and decreased S6 phosphorylation, reducing hepatocellular adenoma. Exercise activated autophagy with increased LC3-II/LC3-I and mitochondrial recruitment of phosphorylated PTEN-induced kinase. Therefore, exercise attenuates the transition from NAFL to NASH, improves biochemical and histological parameters of NAFLD, and impedes the progression of fibrosis and tumorigenesis associated with enhanced activation of AMPK signaling and favors liver autophagy. Our work supports the benefits of exercise independently of dietary changes.
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Affiliation(s)
- Maria Guarino
- Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; (M.G.); (P.K.); (S.G.-M.); (M.V.S.-P.)
- Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy
| | - Pavitra Kumar
- Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; (M.G.); (P.K.); (S.G.-M.); (M.V.S.-P.)
| | - Andrea Felser
- University Institute of Clinical Chemistry, Bern University Hospital, 3010 Bern, Switzerland; (A.F.); (J.-M.N.)
| | | | - Sergi Guixé-Muntet
- Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; (M.G.); (P.K.); (S.G.-M.); (M.V.S.-P.)
| | - Bostjan Humar
- Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, 8091 Zürich, Switzerland;
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, University of Geneva, 1206 Geneva, Switzerland;
| | - Jean-Marc Nuoffer
- University Institute of Clinical Chemistry, Bern University Hospital, 3010 Bern, Switzerland; (A.F.); (J.-M.N.)
| | - Marie V. St-Pierre
- Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; (M.G.); (P.K.); (S.G.-M.); (M.V.S.-P.)
| | - Jean-François Dufour
- Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; (M.G.); (P.K.); (S.G.-M.); (M.V.S.-P.)
- University Clinic of Visceral Surgery and Medicine, Inselspital Bern, 3010 Bern, Switzerland
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29
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Tang X, Li A, Xie C, Zhang Y, Liu X, Xie Y, Wu B, Zhou S, Huang X, Ma Y, Cao W, Xu R, Shen J, Huo Z, Cai S, Liang Y, Ma D. The PI3K/mTOR dual inhibitor BEZ235 nanoparticles improve radiosensitization of hepatoma cells through apoptosis and regulation DNA repair pathway. NANOSCALE RESEARCH LETTERS 2020; 15:63. [PMID: 32219609 PMCID: PMC7099126 DOI: 10.1186/s11671-020-3289-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 02/27/2020] [Indexed: 05/05/2023]
Abstract
Polymer materials encapsulating drugs have broad prospects for drug delivery. We evaluated the effectiveness of polyethylene glycol-poly (lactic-co-glycolic acid) (PLGA-PEG) encapsulation and release characteristics of PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235). We proposed a strategy for targeting radiosensitization of liver cancer cells. The biocompatibility, cell interaction, and internalization of Glypican-3 (GPC3) antibody-modified, BEZ235-loaded PLGA-PEG nanoparticles (NP-BEZ235-Ab) in hepatoma cells in vitro were studied. Also, the cell killing effect of NP-BEZ235-Ab combined with γ-ray cell was evaluated. We used confocal microscopy to monitor nanoparticle-cell interactions and cellular uptake, conducted focus-formation experiments to analyze the synergistic biological effects of NP-BEZ235-Ab and priming, and studied synergy in liver cancer cells using molecular biological methods such as western blotting. We found that PLGA-PEG has good loading efficiency for BEZ235 and high selectivity to GPC3-positive HepG2 liver cancer cells, thus documenting that NP-BEZ235-Ab acts as a small-molecule drug delivery nanocarrier. At the nominal concentration, the NP-BEZ235-Ab nanoformulation synergistically kills liver cancer cells with significantly higher efficiency than does the free drug. Thus, NP-BEZ235-Ab is a potential radiosensitizer.
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Affiliation(s)
- Xiaolong Tang
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Amin Li
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Chunmei Xie
- Blood Transfusion Department, Guangzhou 8th People's Hospital, Guangzhou Medical University, Guangzhou, 510632, People's Republic of China
| | - Yinci Zhang
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Xueke Liu
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Yinghai Xie
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Binquan Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, People's Republic of China
| | - Shuping Zhou
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Xudong Huang
- Department of Interventional, Affiliated Oriental Hospital, Anhui University of Technology, Huainan, 232003, People's Republic of China
| | - Yongfang Ma
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Weiya Cao
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Ruyue Xu
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Jing Shen
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Zhen Huo
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Shuyu Cai
- Huainan First People's Hospital and First Affiliated Hospital of Medical School, Anhui University of Science and Technology, Huainan, 232001, People's Republic of China
| | - Yong Liang
- Huai'an Hospital Affiliated of Xuzhou Medical College and Huai'an Second Hospital, Huai'an, 223002, People's Republic of China.
| | - Dong Ma
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, People's Republic of China.
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30
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Berkan-Kawińska A, Piekarska A. Hepatocellular carcinoma in non-alcohol fatty liver disease - changing trends and specific challenges. Curr Med Res Opin 2020; 36:235-243. [PMID: 31631714 DOI: 10.1080/03007995.2019.1683817] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background and Aims: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. The etiology of this disease is known in 90% of the patients, and it is viral in most of the cases. According to recent predictions, nearly half of the world population will be suffering from obesity by 2030. Consequently, non-alcoholic fatty liver disease (NAFLD) may play a growing role in HCC epidemiology. In this review, we sought to explore the relationship between liver steatosis and HCC.Methods: A narrative review was conducted using the PubMed MeSH search. The eligible papers were identified using a standard PubMed search with relevant key terms and various synonyms.Results: According to the results, patients with NAFLD-HCC tended to be older than those with hepatitis C virus (HCV)-HCC, and they were more often obese and had concomitant diseases, such as diabetes. On the other hand, the synthetic liver function was better preserved in NAFLD-HCC patients, who also obtained lower scores on the Model for End-stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP). However, it has to be noted that HCC in patients with non-alcoholic steatohepatitis (NASH) may develop without underlying cirrhosis. Although NASH-HCC is usually smaller and well-differentiated compared to HCV-HCC, the prognosis is similar in both groups. Efficient HCC screening in NASH cirrhosis poses a challenge because it is difficult to perform ultrasound examination in obese patients and alfa-fetoprotein level is no longer considered reliable.Conclusions: The constantly increasing prevalence of NAFLD in the general population can contribute to a growing role of NAFLD/NASH in HCC epidemiology. Moreover, some particular challenges specific for patients with liver steatosis may impede proper HCC diagnosis, treatment and follow-up.
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Affiliation(s)
| | - Anna Piekarska
- Infectious Diseases and Hepatology Department, Medical University of Lodz, Lodz, Poland
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Affiliation(s)
- Maria Guarino
- Hepatology, Department for BioMedical Research, University of Bern, Bern, Switzerland.,Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Cedric Bovet
- University Institute of Clinical Chemistry, Inselspital, University of Bern, Bern, Switzerland
| | - Jean-François Dufour
- Hepatology, Department for BioMedical Research, University of Bern, Bern, Switzerland.,University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
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