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Nakazawa S, Furuya Y, Sakai K, Fukai K, Sano K, Hoshi K, Kojimahara N, Toyota A, Korenaga M, Tatemichi M. Association among occupational class, alcohol consumption, and the risk of hospitalisations due to alcoholic liver diseases: a matched case-control study. BMC Public Health 2025; 25:1445. [PMID: 40247308 PMCID: PMC12004761 DOI: 10.1186/s12889-025-22715-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 04/09/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND This study aimed to identify the occupational class and specific occupations associated with hospitalisations due to alcohol-related liver disease and alcoholic liver cirrhosis, based on the distribution of alcohol consumption. METHODS This matched case-control study used a nationwide, multicentre, inpatient dataset from the Inpatient Clinico-Occupational Database of the Rosai Hospital Group in Japan. A total of 5,490 cases with alcohol-related liver disease and 10,961 controls were included in this study. Participants were categorised according to occupational class (blue-collar, service, professional, and manager) and industrial sector (blue-collar, service, and white-collar). Professionals in white-collar industries were set as the reference group. We calculated the odds ratios (ORs) and confidence intervals (CIs) of alcohol-related liver disease and alcoholic liver cirrhosis using conditional logistic regression models. RESULTS Blue-collar workers and service workers in both the service and blue-collar industries had a higher risk of hospitalisations due to alcohol-related liver disease: The ORs (95% CIs) for alcohol-related liver disease were 1.33 (1.15-1.55) for blue-collar workers in the blue-collar industry, 1.21 (1.03-1.42) for service workers in the blue-collar industry, 1.23 (1.01-1.51) for blue-collar workers in the service industry, and 1.47 (1.25-1.72) for service workers in the service industry. Among service workers, food and drink preparatory workers and customer service workers had a higher risk of hospitalisations due to alcohol-related liver disease and alcoholic liver cirrhosis compared to professionals (reference group), with ORs of 2.28 (1.81-2.89) and 2.18 (1.64-2.89), respectively, for alcohol-related liver disease. Among blue-collar workers, skeleton construction workers had a higher risk of hospitalisations due to alcohol-related liver disease, with an OR of 2.31 (1.63-3.3). Workers in occupations with a high risk of hospitalisations due to alcohol-related liver disease had higher percentages of alcohol consumption compared to professionals. CONCLUSIONS Occupational class and specific jobs were associated with the risk of hospitalisations due to alcohol-related liver disease and alcoholic liver cirrhosis, with alcohol consumption patterns contributing to this increased risk.
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Affiliation(s)
- Shoko Nakazawa
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Yuko Furuya
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kosuke Sakai
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan.
| | - Kei Sano
- Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan
| | - Keika Hoshi
- Center for Health Informatics Policy, National Institute of Public Health, Wako, Japan
- Department of Hygiene, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Noriko Kojimahara
- Department of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
| | - Akihiro Toyota
- Chugoku Rosai Hospital Research Center for the Promotion of Health and Employment Support, Japan Organization of Occupational Health and Safety, Hiroshima, Japan
| | - Masaaki Korenaga
- Hepatitis Information Center, The Research Center for Hepatitis and Immunology, National Institute of Global Health and Medicine, Japan Institute for Health Security, Ichikawa, Japan
| | - Masayuki Tatemichi
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
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Cheraghpour M, Hatami B, Singal AG. Lifestyle and Pharmacologic Approaches to Prevention of Metabolic Dysfunction-associated Steatotic Liver Disease-related Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2025; 23:685-694.e6. [PMID: 39800201 DOI: 10.1016/j.cgh.2024.09.041] [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: 08/03/2024] [Revised: 09/19/2024] [Accepted: 09/30/2024] [Indexed: 01/15/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate pharmacologic approach for individuals with MASLD may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.
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Affiliation(s)
- Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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Wang CR, Cai D, He K, Hu JJ, Dai X, Zhu Q, Zhong GC. Red Meat, Poultry, and Fish Consumption and the Risk of Liver Cancer: A Prospective Cohort Study of 0.5 Million Chinese Adults. Cancer Epidemiol Biomarkers Prev 2025; 34:412-419. [PMID: 39714249 DOI: 10.1158/1055-9965.epi-24-1158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/08/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND Epidemiological evidence on meat consumption and liver cancer risk is limited and inconclusive; moreover, no prospective study has been conducted to investigate this association in China. Hence, we performed this study to examine the association of red meat, poultry, and fish consumption with the risk of liver cancer in a Chinese population. METHODS A total of 510,048 Chinese adults of ages 30 to 79 years were included and were followed up through December 31, 2016. Red meat, poultry, and fish consumption was evaluated using an interviewer-administered laptop-based questionnaire. HRs and 95% confidence intervals (CI) for liver cancer incidence were calculated using Cox regression. RESULTS Over a mean follow-up of 9.94 years, 1,906 liver cancer cases were observed. Each 50 g/day increase in red meat (HR 0.72; 95% CI, 0.49-1.05), poultry (HR 0.93; 95% CI, 0.83-1.03), and fish (HR 0.95; 95% CI, 0.85-1.05) consumption was not associated with the risk of liver cancer in the whole study population; however, subgroup analysis revealed an inverse association with poultry consumption in rural residents but not in urban residents (Pinteraction = 0.046). The initial associations did not change materially in a series of sensitivity analyses. CONCLUSIONS Red meat and fish consumption is not associated with the risk of liver cancer in this Chinese population. The inverse association with poultry consumption in Chinese rural residents should be interpreted with caution. IMPACT This is the first prospective study examining the association between meat consumption and the risk of liver cancer in the Chinese population.
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Affiliation(s)
- Chun-Rui Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, the Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dong Cai
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kun He
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie-Jun Hu
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Dai
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Guo-Chao Zhong
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Yeo YH, Abdelmalek M, Khan S, Moylan CA, Rodriquez L, Villanueva A, Yang JD. Current and emerging strategies for the prevention of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2025; 22:173-190. [PMID: 39653784 DOI: 10.1038/s41575-024-01021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2024] [Indexed: 01/05/2025]
Abstract
Liver cancer is the third leading cause of cancer-related deaths globally, with incident cases expected to rise from 905,700 in 2020 to 1.4 million by 2040. Hepatocellular carcinoma (HCC) accounts for about 80% of all primary liver cancers. Viral hepatitis and chronic excessive alcohol consumption are major risk factors for HCC, but metabolic dysfunction-associated steatotic liver disease is also becoming a dominant cause. The increasing numbers of cases of HCC and changes in risk factors highlight the urgent need for updated and targeted prevention strategies. Preventive interventions encompass strategies to decrease the burden of chronic liver diseases and their progression to HCC. These strategies include nutritional interventions and medications that have shown promise in preclinical models. Although prevailing approaches focus on treating chronic liver disease, leveraging a wider range of interventions represents a promising area to safeguard at-risk populations. In this Review, we explore existing evidence for preventive strategies by highlighting established and potential paths to reducing HCC risk effectively and safely, especially in individuals with chronic liver diseases. We categorize the preventive strategies by the mechanism of action, including anti-inflammatory, antihyperglycaemic, lipid-lowering, nutrition and dietary, antiviral, and antifibrotic pathways. For each category, we discuss the efficacy and safety information derived from mechanistic, translational, observational and clinical trial data, pinpointing knowledge gaps and directions for future research.
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Affiliation(s)
- Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Manal Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Seema Khan
- Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Cynthia A Moylan
- Division of Gastroenterology, Duke University Health System, Durham, NC, USA
| | - Luz Rodriquez
- Gastrointestinal & Other Cancers Research Group, NCI, Rockville, MD, USA
| | - Augusto Villanueva
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Hu WH, Sun JA, Liu C. Causal associations between dietary habits and liver cancer risk: a two-sample Mendelian randomization study. Discov Oncol 2025; 16:120. [PMID: 39909996 PMCID: PMC11799489 DOI: 10.1007/s12672-025-01885-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/03/2025] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND Liver cancer is among the most prevalent cancers worldwide and is the second leading cause of cancer-related death. Epidemiological evidence suggests a potential correlation between dietary habits and the incidence of liver cancer. However, establishing a definitive causal relationship remains uncertain. Mendelian randomization (MR) is frequently employed to investigate the causal link between exposure and results. AIM This research focuses primarily on exploring and confirming whether there is a causal connection between dietary choices and the risk of liver cancer. METHODS Exposure data, encompassing various dietary habits such as the consumption of dried and fresh fruits, both cooked and raw vegetables, types of fish (oily and nonoily), and beverages such as tea and coffee, as well as different meats (poultry, beef, pork, and processed), were obtained from the UK Biobank. Conversely, outcome data were derived from the FinnGen study. Inverse variance weighting (IVW) was predominantly employed to assess the causal relationship. To ensure the validity of our findings, rigorous tests for heterogeneity and horizontal pleiotropy were conducted. RESULTS Our MR study findings revealed a significant association, indicating that genetically influenced oily fish intake is linked to a lower risk of liver cancer (OR = 0.160, 95% CI 0.026-0.968; P = 0.046). However, no substantial causal connections between liver cancer and the intake of other dietary habits were observed. Importantly, our two-sample MR investigations indicated no considerable pleiotropy effects in the instrumental variables (IVs). CONCLUSION In summary, our findings suggest a potential protective effect of oily fish intake against liver cancer, emphasizing the need for further studies to validate these results.
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Affiliation(s)
- Wen-Hao Hu
- Department of Emergency, Zhengzhou Central Hospital Affiliated With Zhengzhou University, Henan, Zhengzhou, 450007, China
| | - Jia-An Sun
- Department of Emergency, Zhengzhou Central Hospital Affiliated With Zhengzhou University, Henan, Zhengzhou, 450007, China
| | - Chang Liu
- Department of Emergency, Zhengzhou Central Hospital Affiliated With Zhengzhou University, Henan, Zhengzhou, 450007, China.
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Huang X, Zhang X, Hao X, Wang T, Wu P, Shen L, Yang Y, Wan W, Zhang K. Association of dietary quality and mortality in the non-alcoholic fatty liver disease and advanced fibrosis populations: NHANES 2005-2018. Front Nutr 2025; 12:1507342. [PMID: 39917744 PMCID: PMC11798782 DOI: 10.3389/fnut.2025.1507342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) has emerged as a significant global health concern, with advanced fibrosis increasing mortality risks. Despite the abundance of dietary guidelines for managing NAFLD, the precise impact of diet quality on mortality among individuals with advanced fibrosis remains elusive. This study aims to explore the influence of five dietary quality indexes on mortality among NAFLD patients and advanced fibrosis patients. Methods This study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2005 to 2018 to assess dietary quality based on the Alternate Mediterranean Diet (aMED), Healthy Eating Index-2020 (HEI-2020), Dietary Approach to Stop Hypertension (DASH), Alternate Healthy Eating Index (AHEI), and Dietary Inflammatory Index (DII). Weighted Cox proportional hazard regression models along with restricted cubic splines and subgroup analyses were employed in this study. Results The analysis encompassed 3,634 NAFLD patients. After a median follow-up of 89 months, it was found that higher scores on the aMED (HR 0.814, 95% CI 0.681-0.972), HEI-2020 (HR 0.984, 95% CI 0.972-0.997), DASH (HR 0.930, 95% CI 0.883-0.979), and AHEI (HR 0.980, 95% CI 0.966-0.995) were associated with lower mortality risks, while DII scores (HR 1.280, 95% CI 1.098-1.493) indicated an increased risk of mortality. Additionally, a nonlinear relationship was identified solely between AHEI scores and all-cause mortality in NAFLD patients. Notably, among patients with advanced fibrosis, HEI-2020 as a categorical variable (T3: HR 0.519, 95% CI 0.280-0.964), DASH as a continuous variable (continuous: HR 0.921, 95% CI 0.849-0.999), AHEI (continuous: HR 0.971, 95% CI 0.945-0.997; T2: HR 0.545, 95% CI 0.310-0.960; T3: HR 0.444, 95% CI 0.245-0.804), and DII (continuous: HR 1.311, 95% CI 1.121-1.534; T3: HR 2.772, 95% CI 1.477-5.202) exhibited significant associations with all-cause mortality. Subgroup analyses revealed an interaction between AHEI scores and sex among NAFLD patients, where higher AHEI scores correlated with lower all-cause mortality in females, but no such association was observed in males. For other dietary quality, subgroup analyses indicated that their relationships with mortality were robust. Conclusion Our study suggests that a high-quality diet could potentially mitigate mortality risk in both NAFLD and advanced fibrosis patients.
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Affiliation(s)
- Xingyong Huang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaoyue Zhang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xuanyu Hao
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tingting Wang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Peng Wu
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lufan Shen
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuanyuan Yang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wenyu Wan
- Key Laboratory of Immunodermatology, Ministry of Education, Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Immunodermatology, National Health Commission of the People's Republic of China, The First Hospital of China Medical University, Shenyang, China
- National and Local Joint Engineering Research Center of Immunodermatological Theranostics, The First Hospital of China Medical University, Shenyang, China
| | - Kai Zhang
- Department of Gastroenterology, Endoscopic Center, Shengjing Hospital of China Medical University, Shenyang, China
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Song J, Huang Y, Liu L, Hui D, Wang Z, Xie D, Jiang Y, Cao H, Dai Y, Ye G, Su S, Zhou M, Zhang Q, Sun M. Integrated metabolomics and network pharmacology to explore the clinical efficacy and mechanism of Yinchenhao decoction combined with nucleoside analogues on chronic hepatitis B. J Pharm Biomed Anal 2024; 253:116513. [PMID: 39461066 DOI: 10.1016/j.jpba.2024.116513] [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: 06/06/2024] [Revised: 09/26/2024] [Accepted: 10/06/2024] [Indexed: 10/29/2024]
Abstract
Yinchenhao decoction (YCHD) is widely used in the treatment of damp-heat syndrome of chronic hepatitis B (CHB), but it remains unclear about the active compounds in YCHD and its potential mechanism for treating CHB. The purpose of this work is to evaluate the clinical efficacy of YCHD combined with nucleoside analogues (NAs) for the treatment of CHB. Besides, based on the exact clinical efficacy, we combined serum metabolomics and network pharmacology to screen differential metabolites and related pathways regulated by YCHD to investigate the possible mechanism for treating CHB. It revealed that NAs plus YCHD could significantly improve alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, increase HBV-DNA negative rate (P<0.05), reduce the levels of inflammatory factors and LSM (both P<0.05), regulate lipids (P<0.05), and improve the symptoms of traditional Chinese medicine (TCM) (P<0.05) in CHB patients. YCHD was relatively safe. It showed 30 active compounds including chlorogenic acid, geniposide, emodin, quercetin, kaempferol, β-sitosterol and aloe emodin, and 115 key targets which were related to the regulation of lipids and reduction of oxidative stress related to the effect of YCHD in CHB in the network pharmacology analysis. We found 9 core targets and 4 key metabolites according to metabolomics, which were partly consistent with the network pharmacology findings. It proved that network pharmacology combined with metabolomics can well explain the "multi-component-multi-target" mechanism of complex TCM.
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Affiliation(s)
- Jingru Song
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yanping Huang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of GCP,Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Lu Liu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Dengcheng Hui
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zheng Wang
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Dong Xie
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yulang Jiang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hongyan Cao
- Shanghai University of TCM, Shanghai TCM-integrated Hospital, China
| | - Yancheng Dai
- Shanghai University of TCM, Shanghai TCM-integrated Hospital, China
| | - Guan Ye
- Central Research Institute, Shanghai Pharmaceuticals Holding Co.,Ltd., Shanghai 201203, China
| | - Shibing Su
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Mingmei Zhou
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Qin Zhang
- Department of GCP,Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
| | - Mingyu Sun
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Lin Y, Li R, Li T, Zhao W, Ye Q, Dong C, Gao Y. A prognostic model for hepatocellular carcinoma patients based on polyunsaturated fatty acid-related genes. ENVIRONMENTAL TOXICOLOGY 2024; 39:4649-4668. [PMID: 38682322 DOI: 10.1002/tox.24273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/19/2024] [Accepted: 03/23/2024] [Indexed: 05/01/2024]
Abstract
OBJECTIVE Polyunsaturated fatty acids (PUFAs) have attracted increasing attention for their role in liver cancer development. The objective of this study is to develop a prognosis prediction model for patients with liver cancer based on PUFA-related metabolic gene characteristics. METHOD Transcriptome data and clinical data were obtained from public databases, while gene sets related to PUFAs were acquired from the gene set enrichment analysis (GSEA) database. Univariate Cox analysis was conducted on the training set, followed by LASSO logistic regression and multivariate Cox analysis on genes with p < .05. Subsequently, the stepwise Akaike information criterion method was employed to construct the model. The high- and low-risk groups were divided based on the median score, and the model's survival prediction ability, diagnostic efficiency, and risk score distribution of clinical features were validated. The above procedures were also validated in the validation set. Immune infiltration levels were evaluated using four algorithms, and the immunotherapeutic potential of different groups was explored. Significant enrichment pathways among different groups were selected based on the GSEA algorithm, and mutation analyses were conducted. Nomogram prognostic models were constructed by incorporating clinical factors and risk scores using univariate and multivariate Cox regression analysis, validated through calibration curves and clinical decision curves. Additionally, sensitivity analysis of drugs was performed to screen potential targeted drugs. RESULTS We constructed a prognostic model comprising eight genes (PLA2G12A, CYP2C8, ABCCI, CD74, CCR7, P2RY4, P2RY6, and YY1). Validation across multiple datasets indicated the model's favorable prognostic prediction ability and diagnostic efficiency, with poorer grading and staging observed in the high-risk group. Variations in mutation status and pathway enrichment were noted among different groups. Incorporating Stage, Grade, T.Stage, and RiskScore into the nomogram prognostic model demonstrated good accuracy and clinical decision benefits. Multiple immune analyses suggested greater benefits from immunotherapy in the low-risk group. We predicted multiple targeted drugs, providing a basis for drug development. CONCLUSION Our study's multifactorial prognostic model across multiple datasets demonstrates good applicability, offering a reliable tool for personalized therapy. Immunological and mutation-related analyses provide theoretical foundations for further research. Drug predictions offer important insights for future drug development and treatment strategies. Overall, this study provides comprehensive insights into tumor prognosis assessment and personalized treatment planning.
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Affiliation(s)
- Yun Lin
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Ruihao Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Tong Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Wenrong Zhao
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Qianling Ye
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Chunyan Dong
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Yong Gao
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
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Li X, Hu Z, Shi Q, Qiu W, Liu Y, Liu Y, Huang S, Liang L, Chen Z, He X. Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression. Oncogene 2024; 43:3121-3136. [PMID: 39251845 DOI: 10.1038/s41388-024-03150-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 08/28/2024] [Accepted: 08/30/2024] [Indexed: 09/11/2024]
Abstract
An increase in the total choline-containing compound content is a common characteristic of cancer cells, and aberrant choline metabolism in cancer is closely associated with malignant progression. However, the potential role of choline-induced global transcriptional changes in cancer cells remains unclear. In this study, we reveal that an elevated choline content facilitates hepatocellular carcinoma (HCC) cell proliferation by reprogramming Krüppel-like factor 5 (KLF5)-dominated core transcriptional regulatory circuitry (CRC). Mechanistically, choline administration leads to elevated S-adenosylmethionine (SAM) levels, inducing the formation of H3K4me1 within the super-enhancer (SE) region of KLF5 and activating its transcription. KLF5, as a key transcription factor (TF) of CRC established by choline, further transactivates downstream genes to facilitate HCC cell cycle progression. Additionally, KLF5 can increase the expression of choline kinase-α (CHKA) and CTP:phosphocholine cytidylyltransferase (CCT) resulting in a positive feedback loop to promote HCC cell proliferation. Notably, the histone deacetylase inhibitor (HDACi) vorinostat (SAHA) significantly suppressed KLF5 expression and liver tumor growth in mice, leading to a prolonged lifespan. In conclusion, these findings highlight the epigenetic regulatory mechanism of the SE-driven key regulatory factor KLF5 conducted by choline metabolism in HCC and suggest a potential therapeutic strategy for HCC patients with high choline content.
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Affiliation(s)
- Xinrong Li
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhixiang Hu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qili Shi
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenying Qiu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yizhe Liu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanfang Liu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shenglin Huang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Linhui Liang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiao Chen
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Xianghuo He
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
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10
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Shu W, Liu L, Jiang J, Yao Q. Dietary patterns and hepatocellular carcinoma risk: a systematic review and meta-analysis of cohort and case-control studies. Nutr Metab (Lond) 2024; 21:47. [PMID: 38992637 PMCID: PMC11241793 DOI: 10.1186/s12986-024-00822-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 06/26/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Globally, HCC presents a significant health burden, characterized by high incidence and mortality rates. Epidemiological studies have increasingly suggested a link between dietary patterns and the risk of hepatocellular carcinoma (HCC), yet consensus on this relationship remains elusive. OBJECTIVE This study aims to synthesize existing literature and provide a comprehensive analysis of the association between dietary patterns and HCC risk through meta-analytical methods. METHODS A systematic search of PubMed, Embase, and the Cochrane Library databases was conducted to identify studies examining common dietary patterns in relation to HCC, published up to August 2023. Study quality was rigorously evaluated using the Newcastle-Ottawa Scale. We employed a random effects model to synthesize effect sizes, calculating hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS We identified 13 papers, of these 10 investigating a priori dietary patterns(index-based dietary patterns) and 3 focusing on a posterior dietary patterns (data-driven dietary patterns). Analysis of a priori dietary patterns revealed that higher scores in the Healthy Eating Index (HEI) & alternative HEI (HR = 0.67, 95% CI: 0.54-0.85), Dietary Approaches to Stop Hypertension (DASH) (HR = 0.77, 95% CI: 0.66-0.91), and the Mediterranean diet (HR = 0.65, 95% CI: 0.56-0.75) were associated with a reduced risk of HCC. Conversely, pro-inflammatory dietary patterns were linked with an increased risk (HR = 2.21, 95% CI: 1.58-3.09). In a posterior dietary patterns, a vegetable-based diet was negatively correlated with HCC risk (HR = 0.63, 95% CI: 0.49-0.81). CONCLUSION This meta-analysis underscores a significant association between dietary patterns and the risk of HCC. Adherence to healthy dietary patterns characterized by high in vegetables, whole grains, legumes, nuts, and low in red and processed meats may confer a protective effect against HCC, whereas inflammatory diets appear to elevate risk.
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Affiliation(s)
- Wenxi Shu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Ling Liu
- The Second Affiliated Hospital of Zhejiang, Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou, 310005, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Jiaojiao Jiang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Qinghua Yao
- The Second Affiliated Hospital of Zhejiang, Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou, 310005, Zhejiang, China.
- Key Research Laboratory of the Pathological Mechanism of Intestinal Disease 'Inflammation-Cancer' Transformation, Zhejiang, 310005, China.
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11
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Su F, Koeberle A. Regulation and targeting of SREBP-1 in hepatocellular carcinoma. Cancer Metastasis Rev 2024; 43:673-708. [PMID: 38036934 PMCID: PMC11156753 DOI: 10.1007/s10555-023-10156-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/10/2023] [Indexed: 12/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.
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Affiliation(s)
- Fengting Su
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Andreas Koeberle
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria.
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12
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Ali AH, Hachem M, Ahmmed MK. Docosahexaenoic acid-loaded nanoparticles: A state-of-the-art of preparation methods, characterization, functionality, and therapeutic applications. Heliyon 2024; 10:e30946. [PMID: 38774069 PMCID: PMC11107210 DOI: 10.1016/j.heliyon.2024.e30946] [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] [Received: 10/16/2023] [Revised: 05/08/2024] [Accepted: 05/08/2024] [Indexed: 05/24/2024] Open
Abstract
Docosahexaenoic acid (DHA, C22:6 n-3), an omega-3 polyunsaturated fatty acid, offers several beneficial effects. DHA helps in reducing depression, autoimmune diseases, rheumatoid arthritis, attention deficit hyperactivity syndrome, and cardiovascular diseases. It can stimulate the development of brain and nerve, alleviate lipids metabolism-related disorders, and enhance vision development. However, DHA susceptibility to chemical oxidation, poor water solubility, and unpleasant order could restrict its applications for nutritional and therapeutic purposes. To avoid these drawbacks and enhance its bioavailability, DHA can be encapsulated using an effective delivery system. Several encapsulation methods are recognized, and DHA-loaded nanoparticles have demonstrated numerous benefits. In clinical studies, positive influences on the development of several diseases have been reported, but some assumptions are conflicting and need more exploration, since DHA has a systemic and not a targeted release at the required level. This might cause the applications of nanoparticles that could allow DHA release at the required level and improve its efficiency, thus resulting in a better controlling of several diseases. In the current review, we focused on researches investigating the formulation and development of DHA-loaded nanoparticles using different delivery systems, including low-density lipoprotein, zinc oxide, silver, zein, and resveratrol-stearate. Silver-DHA nanoparticles presented a typical particle size of 24 nm with an incorporation level of 97.67 %, while the entrapment efficiency of zinc oxide-DHA nanoparticles represented 87.3 %. By using zein/Poly (lactic-co-glycolic acid) stabilized nanoparticles, DHA's encapsulation level reached 84.6 %. We have also highlighted the characteristics, functionality and medical implementation of these nanoparticles in the treatment of inflammations, brain disorders, diabetes as well as hepatocellular carcinoma.
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Affiliation(s)
- Abdelmoneim H. Ali
- Department of Chemical and Petroleum Engineering, Khalifa University of Science and Technology, Abu Dhabi, 127788, United Arab Emirates
| | - Mayssa Hachem
- Department of Chemistry and Healthcare Engineering Innovation Group, Khalifa University of Sciences and Technology, Abu Dhabi, 127788, United Arab Emirates
| | - Mirja Kaizer Ahmmed
- Department of Fishing and Post-harvest Technology, Chattogram Veterinary and Animal Sciences University, Chattogram, Bangladesh
- Riddet Institute, Massey University, Palmerston North, New Zealand
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13
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Akbar S, Rahman A, Ahmad N, Imran M, Hafeez Z. Understanding the Role of Polyunsaturated Fatty Acids in the Development and Prevention of Cancer. Cancer Treat Res 2024; 191:57-93. [PMID: 39133404 DOI: 10.1007/978-3-031-55622-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Polyunsaturated fatty acids (PUFAs), notably omega-3 (n-3) and omega-6 (n-6), have received much attention owing to their multifaceted effects not only in the management of diverse pathological conditions but also in the maintenance of overall health of an individual. A disproportionately high n-6 to n-3 ratio contributes to the development of various disorders including cancer, which ranks as a leading cause of death worldwide with profound social and economic burden. Epidemiological studies and clinical trials combined with the animal and cell culture models have demonstrated the beneficial effects of n-3 PUFAs in reducing the risk of various cancer types including breast, prostate and colon cancer. The anti-cancer actions of n-3 PUFAs are mainly attributed to their role in the modulation of a wide array of cellular processes including membrane dynamics, apoptosis, inflammation, angiogenesis, oxidative stress, gene expression and signal transduction pathways. On the contrary, n-6 PUFAs have been shown to exert pro-tumor actions; however, the inconsistent findings and controversial data emphasize upon the need to further investigation. Nevertheless, one of the biggest challenges in future is to optimize the n-6 to n-3 ratio despite the genetic predisposition, age, gender and disease severity. Moreover, a better understanding of the potential risks and benefits as well as the cellular and molecular mechanisms of the basic actions of these PUFAs is required to explore their role as adjuvants in cancer therapy. All these aspects will be reviewed in this chapter.
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Affiliation(s)
- Samina Akbar
- CALBINOTOX, Université de Lorraine, 54000, Nancy, France.
| | - Abdur Rahman
- Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Nazir Ahmad
- Faculty of Life Sciences, Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Imran
- Department of Biosciences, Faculty of Sciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan
| | - Zeeshan Hafeez
- CALBINOTOX, Université de Lorraine, 54000, Nancy, France
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14
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Machado MV. MASLD treatment-a shift in the paradigm is imminent. Front Med (Lausanne) 2023; 10:1316284. [PMID: 38146424 PMCID: PMC10749497 DOI: 10.3389/fmed.2023.1316284] [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: 10/10/2023] [Accepted: 11/24/2023] [Indexed: 12/27/2023] Open
Abstract
MASLD prevalence is growing towards the leading cause of end-stage liver disease. Up to today, the most effective treatment is weight loss. Weight loss interventions are moving from lifestyle changes to bariatric surgery or endoscopy, and, more recently, to a new wave of anti-obesity drugs that can compete with bariatric surgery. Liver-targeted therapy is a necessity for those patients who already present liver fibrosis. The field is moving fast, and in the near future, we will testify to a disruptive change in MASLD treatment, similar to the paradigm-shift that occurred for hepatitis C almost one decade ago with direct antiviral agents.
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Affiliation(s)
- Mariana Verdelho Machado
- Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Hospital de Vila Franca de Xira, Vila Franca de Xira, Portugal
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15
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Lakshimi VI, Kavitha M. New Insights into Prospective Health Potential of ω-3 PUFAs. Curr Nutr Rep 2023; 12:813-829. [PMID: 37996669 DOI: 10.1007/s13668-023-00508-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
PURPOSE OF REVIEW Docosahexaenoic acid and eicosapentaenoic acid are the two essential long-chain ω-3 polyunsaturated fatty acids (ω-3 PUFAs) promoting human health which are obtained from diet or supplementation. The eicosanoids derived from ω-6 and ω-3 PUFAs have opposite characteristics of pro- and anti-inflammatory activities. The proinflammatory effects of ω-6 PUFAs are behind the pathology of the adverse health conditions of PUFA metabolism like cardiovascular diseases, neurological disorders, and inflammatory diseases. A balanced ω-6 to ω-3 ratio of 1-4:1 is critical to prevent the associated disorders. But due to modern agricultural practices, there is a disastrous shift in this ratio to 10-20:1. This review primarily aims to discuss the myriad health potentials of ω-3 PUFAs uncovered through recent research. It further manifests the importance of maintaining a balanced ω-6 to ω-3 PUFA ratio. RECENT FINDINGS ω-3 PUFAs exhibit protective effects against diabetes mellitus-associated complications including diabetic retinopathy, diabetic nephropathy, and proteinuria. COVID-19 is also not an exception to the health benefits of ω-3 PUFAs. Supplementation of ω-3 PUFAs improved the respiratory and clinical symptoms in COVID-19 patients. ω-3 PUFAs exhibit a variety of health benefits including anti-inflammatory property and antimicrobial property and are effective in protecting against various health conditions like atherosclerosis, cardiovascular diseases, diabetes mellitus, COVID-19, and neurological disorders. In the present review, various health potentials of ω-3 PUFAs are extensively reviewed and summarized. Further, the importance of a balanced ω-6 to ω-3 PUFA ratio has been emphasized besides stating the diverse sources of ω-3 PUFA.
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Affiliation(s)
- V Iswareya Lakshimi
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - M Kavitha
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
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16
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Rohwer N, Jelleschitz J, Höhn A, Weber D, Kühl AA, Wang C, Ohno RI, Kampschulte N, Pietzner A, Schebb NH, Weylandt KH, Grune T. Prevention of colitis-induced liver oxidative stress and inflammation in a transgenic mouse model with increased omega-3 polyunsaturated fatty acids. Redox Biol 2023; 64:102803. [PMID: 37392516 DOI: 10.1016/j.redox.2023.102803] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated gut dysfunction, which might also be associated with an inflammatory phenotype in the liver. It is known that the nutritional intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) is inversely correlated to the severity and occurrence of IBD. In order to investigate whether n-3 PUFA can also reduce liver inflammation and oxidative liver damage due to colon inflammation, we explored the dextran sulfate sodium (DSS)-induced colitis model in wild-type and fat-1 mice with endogenously increased n-3 PUFA tissue content. Besides confirming previous data of alleviated DSS-induced colitis in the fat-1 mouse model, the increase of n-3 PUFA also resulted in a significant reduction of liver inflammation and oxidative damage in colitis-affected fat-1 mice as compared to wild-type littermates. This was accompanied by a remarkable increase of established inflammation-dampening n-3 PUFA oxylipins, namely docosahexaenoic acid-derived 19,20-epoxydocosapentaenoic acid and eicosapentaenoic acid-derived 15-hydroxyeicosapentaenoic acid and 17,18-epoxyeicosatetraenoic acid. Taken together, these observations demonstrate a strong inverse correlation between the anti-inflammatory lipidome derived from n-3 PUFA and the colitis-triggered inflammatory changes in the liver by reducing oxidative liver stress.
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Affiliation(s)
- Nadine Rohwer
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology and Diabetes, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany; Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, Brandenburg Medical School and University of Potsdam, Potsdam, Germany; Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Julia Jelleschitz
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Annika Höhn
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), Muenchen-Neuherberg, Germany
| | - Daniela Weber
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Anja A Kühl
- iPATH.Berlin-Immunopathology for Experimental Models, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Chaoxuan Wang
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology and Diabetes, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany; Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, Brandenburg Medical School and University of Potsdam, Potsdam, Germany; Medical Department, Division of Psychosomatic Medicine, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Rei-Ichi Ohno
- University of Wuppertal, Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, Wuppertal, Germany
| | - Nadja Kampschulte
- University of Wuppertal, Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, Wuppertal, Germany
| | - Anne Pietzner
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology and Diabetes, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany; Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
| | - Nils Helge Schebb
- University of Wuppertal, Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, Wuppertal, Germany
| | - Karsten-H Weylandt
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology and Diabetes, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany; Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
| | - Tilman Grune
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), Muenchen-Neuherberg, Germany.
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17
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Kado T, Kusakari N, Tamaki T, Murota K, Tsujiuchi T, Fukushima N. Oleic acid stimulates cell proliferation and BRD4-L-MYC-dependent glucose transporter transcription through PPARα activation in ovarian cancer cells. Biochem Biophys Res Commun 2023; 657:24-34. [PMID: 36965420 DOI: 10.1016/j.bbrc.2023.03.051] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 03/17/2023] [Indexed: 03/27/2023]
Abstract
Fatty acids (FAs) play important roles in cell membrane structure maintenance, energy production via β-oxidation, and as extracellular signaling molecules. Prior studies have demonstrated that exposure of cancer cells to FAs affects cell survival, cell proliferation, and cell motility. Oleic acid (OA) has somewhat controversial effects in cancer cells, with both pro- and anti-cancer effects, depending on cell type. Our prior findings suggested that OA enhances cell survival in serum starved HNOA ovarian cancer cells by activating glycolysis, but not β-oxidation. Here, we pharmacologically examined the cellular mechanisms by which OA stimulates glycolysis in HNOA cells. OA induced cell cycle progression, leading to increase in cell number through peroxisome proliferator activated receptor (PPAR) α activation. OA-induced glycolysis was mediated by increased GLUT expression, and increases in GLUT expression were mediated by increased L-MYC expression. Furthermore, L-MYC expression was due to BRD4 activation. These findings suggested involvement of the BRD4-L-MYC-GLUT axis in OA-stimulated glycolysis. These results suggested that OA could activate PPARα to stimulate two pathways: glycolysis and cell cycle progression, and provided insight into the role of OA in ovarian cancer cell growth.
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Affiliation(s)
- Tsuyoshi Kado
- Division of Molecular Neurobiology, Department of Life Science, Kindai University, Higashiosaka, Japan
| | - Naoki Kusakari
- Division of Molecular Neurobiology, Department of Life Science, Kindai University, Higashiosaka, Japan
| | - Takeru Tamaki
- Division of Molecular Neurobiology, Department of Life Science, Kindai University, Higashiosaka, Japan
| | - Kaeko Murota
- Division of Food and Nutritional Chemistry, Department of Life Science, Kindai University, Higashiosaka, Japan
| | - Toshifumi Tsujiuchi
- Division of Molecular Oncology, Department of Life Science, Kindai University, Higashiosaka, Japan
| | - Nobuyuki Fukushima
- Division of Molecular Neurobiology, Department of Life Science, Kindai University, Higashiosaka, Japan.
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18
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Leineweber CG, Rabehl M, Pietzner A, Rohwer N, Rothe M, Pech M, Sangro B, Sharma R, Verslype C, Basu B, Sengel C, Ricke J, Schebb NH, Weylandt KH, Benckert J. Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma. Front Pharmacol 2023; 14:1124214. [PMID: 36937889 PMCID: PMC10020374 DOI: 10.3389/fphar.2023.1124214] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.
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Affiliation(s)
- Can G. Leineweber
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Miriam Rabehl
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
| | - Anne Pietzner
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
| | - Nadine Rohwer
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | | | - Maciej Pech
- Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, Germany
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Chris Verslype
- Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Bristi Basu
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom
| | - Christian Sengel
- Radiology Department, Grenoble University Hospital, La Tronche, France
| | - Jens Ricke
- Department of Radiology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Nils Helge Schebb
- Chair of Food Chemistry, Faculty of Mathematics and Natural Science, University of Wuppertal, Wuppertal, Germany
| | - Karsten-H. Weylandt
- Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
| | - Julia Benckert
- Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Berlin, Germany
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19
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Cossiga V, Cazzagon N, Montalti R, Ciminnisi S, Attanasio MR, Pezzato F, Giacchetto M, Guarino M, Calvaruso V, Floreani A, Morisco F. The unhealthy lifestyle in primary biliary cholangitis: An enemy to fight. Dig Liver Dis 2022; 55:778-784. [PMID: 36593159 DOI: 10.1016/j.dld.2022.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 10/29/2022] [Accepted: 12/08/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIM Metabolic dysfunctions, particularly hyperlipidemia, are a common finding in Primary Biliary Cholangitis (PBC). In presence of metabolic components of fatty-liver-disease (MAFLD), the liver fibrosis progression risk is higher. The aim of this study was to evaluate lifestyle of PBC patients compared to controls. METHODS In a prospective, multicenter study 107 PBC patients were enrolled; among these, 54 subjects were age-and sex-matched with 54 controls with a propensity-score-matching-analysis. Eating habits and physical activity were evaluated, respectively, with a food-frequency-questionnaire and with a short pre-validated-questionnaire. The adherence to Mediterranean diet was assessed with the alternate Mediterranean diet score. RESULTS The total fat intake was higher in controls than in PBC (p=0.004), unless above the national recommendations in both groups. Moreover, in PBC monounsaturated-fat and polyunsaturated-fatty-acid intakes and the adherence to Mediterranean diet were significantly lower than in controls (p<0.001, p=0.005 and p<0.001 respectively). Regarding physical activity, PBC subjects had a sedentary behavior as well as controls. CONCLUSIONS The lifestyle of both PBC and controls is at high risk of developing MAFLD. Therefore, hepatologists should regularly evaluate eating habits and physical activity in PBC patients and promote a lifestyle change to reduce liver disease progression risk.
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Affiliation(s)
- Valentina Cossiga
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology Unit, University of Naples "Federico II", Naples, Italy.
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Gastroenterology Unit, Azienda Ospedale-Università Padova, Padova, Italy
| | - Roberto Montalti
- Department of Public Health, Division of Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery, University of Naples "Federico II", Naples, Italy
| | - Stefania Ciminnisi
- Gastrointestinal and Liver Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maria Rosaria Attanasio
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology Unit, University of Naples "Federico II", Naples, Italy
| | - Francesco Pezzato
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Marco Giacchetto
- Gastrointestinal and Liver Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology Unit, University of Naples "Federico II", Naples, Italy
| | - Vincenza Calvaruso
- Gastrointestinal and Liver Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology Unit, University of Naples "Federico II", Naples, Italy
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20
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The Polyunsaturated Fatty Acid EPA, but Not DHA, Enhances Neurotrophic Factor Expression through Epigenetic Mechanisms and Protects against Parkinsonian Neuronal Cell Death. Int J Mol Sci 2022; 23:ijms232416176. [PMID: 36555817 PMCID: PMC9788369 DOI: 10.3390/ijms232416176] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/28/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
ω-3 Polyunsaturated fatty acids (PUFAs) have been found to exert many actions, including neuroprotective effects. In this regard, the exact molecular mechanisms are not well understood. Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. Emerging evidence supports the hypothesis that PD is the result of complex interactions between genetic abnormalities, environmental toxins, mitochondrial dysfunction, and other cellular processes, such as DNA methylation. In this context, BDNF (brain-derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) have a pivotal role because they are both involved in neuron differentiation, survival, and synaptogenesis. In this study, we aimed to elucidate the potential role of two PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and their effects on BDNF and GDNF expression in the SH-SY5Y cell line. Cell viability was determined using the MTT assay, and flow cytometry analysis was used to verify the level of apoptosis. Transmission electron microscopy was performed to observe the cell ultrastructure and mitochondria morphology. BDNF and GDNF protein levels and mRNA were assayed by Western blotting and RT-PCR, respectively. Finally, methylated and hydroxymethylated DNA immunoprecipitation were performed in the BDNF and GDNF promoter regions. EPA, but not DHA, is able (i) to reduce the neurotoxic effect of neurotoxin 6-hydroxydopamine (6-OHDA) in vitro, (ii) to re-establish mitochondrial function, and (iii) to increase BNDF and GDNF expression via epigenetic mechanisms.
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21
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Wang Y, Li J, do Vale GD, Chaudhary J, Anwar A, McDonald JG, Qin T, Zhang H, Corbin IR. Repeated trans-arterial treatments of LDL-DHA nanoparticles induce multiple pathways of tumor cell death in hepatocellular carcinoma bearing rats. Front Oncol 2022; 12:1052221. [PMID: 36505796 PMCID: PMC9730405 DOI: 10.3389/fonc.2022.1052221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/07/2022] [Indexed: 11/27/2022] Open
Abstract
Introduction Repeated hepatic arterial delivery of therapeutic agents to the liver by percutaneously implanted port-catheter systems has been widely used to treat unresectable liver cancer. This approach is applied to assess the therapeutic efficacy of repeated low-density lipoprotein-docosahexaenoic acid (LDL-DHA) nanoparticle treatments in a rat model of hepatocellular carcinoma. Methods N1S1 hepatoma bearing rats underwent placement of a percutaneously implanted hepatic artery port-catheter system and were allocated to untreated, control LDL-triolein (LDL-TO) or LDL-DHA nanoparticle infusions groups. Treatments were performed every three days over a nine day study period. MRI was performed at baseline and throughout the study. At the end of the study tissue samples were collected for analyses. Results and Discussion Implantation of the port catheters was successful in all rats. MRI showed that repeated infusions of LDL-DHA nanoparticles significantly impaired the growth of the rat hepatomas eventually leading to tumor regression. The tumors in the LDL-TO treated group showed delayed growth, while the untreated tumors grew steadily throughout the study. Histopathology and MRI support these findings demonstrating extensive tumor necrosis in LDL-DHA treated groups while the control groups displayed minor necrosis. Molecular and biochemical analyses also revealed that LDL-DHA treated tumors had increased levels of nuclear factor-kappa B and lipid peroxidation and depletion of glutathione peroxidase 4 relative to the control groups. Evidence of both ferroptosis and apoptosis tumor cell death was observed following LDL-DHA treatments. In conclusion repeated transarterial infusions of LDL-DHA nanoparticles provides sustained repression of tumor growth in a rat hepatoma model.
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Affiliation(s)
- Yuzhu Wang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, China
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Junjie Li
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Goncalo Dias do Vale
- Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Jaideep Chaudhary
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Arnida Anwar
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Jeffrey G. McDonald
- Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Tao Qin
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, China
| | - Hongwei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, China
| | - Ian R. Corbin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
- Internal Medicine Division of Liver and Digestive Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
- Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
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22
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Abstract
Liver cancer, mainly hepatocellular carcinoma (HCC), remains a major cause of cancer-related death worldwide. With the global epidemic of obesity, the major HCC etiologies have been dynamically shifting from viral to metabolic liver diseases. This change has made HCC prevention difficult with increasingly elusive at-risk populations as rational target for preventive interventions. Besides ongoing efforts to reduce obesity and metabolic disorders, chemoprevention in patients who already have metabolic liver diseases may have a significant impact on the poor HCC prognosis. Hepatitis B- and hepatitis C-related HCC incidences have been substantially reduced by the new antivirals, but HCC risk can persist over a decade even after successful viral treatment, highlighting the need for HCC-preventive measures also in these patients. Experimental and retrospective studies have suggested potential utility of generic agents such as lipophilic statins and aspirin for HCC chemoprevention given their well-characterized safety profile, although anticipated efficacy may be modest. In this review, we overview recent clinical and translational studies of generic agents in the context of HCC chemoprevention under the contemporary HCC etiologies. We also discuss newly emerging approaches to overcome the challenges in clinical testing of the agents to facilitate their clinical translation.
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Affiliation(s)
- Fahmida Rasha
- Liver Tumor Translational Research Program; Simmons Comprehensive Cancer Center; Division of Digestive and Liver Diseases; Department of Internal Medicine; University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Subhojit Paul
- Liver Tumor Translational Research Program; Simmons Comprehensive Cancer Center; Division of Digestive and Liver Diseases; Department of Internal Medicine; University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tracey G Simon
- Liver Center, Division of Gastroenterology, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yujin Hoshida
- Liver Tumor Translational Research Program; Simmons Comprehensive Cancer Center; Division of Digestive and Liver Diseases; Department of Internal Medicine; University of Texas Southwestern Medical Center, Dallas, TX, USA
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23
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Zheng J, Zhao L, Dong J, Chen H, Li D, Zhang X, Hassan MM, Steck SE, Li X, Xiang YB, Wang H. The role of dietary factors in nonalcoholic fatty liver disease to hepatocellular carcinoma progression: A systematic review. Clin Nutr 2022; 41:2295-2307. [PMID: 36096063 DOI: 10.1016/j.clnu.2022.08.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/09/2022] [Accepted: 08/16/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Dietary factors play an important role in promoting nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) development through regulation of metabolism and inflammation. However, so far there was no evidence regarding how dietary factors may influence different disease outcomes in the NAFLD to HCC progression. Our study aimed to comprehensively evaluate the role of dietary factors on the risk of progression from NAFLD to HCC. METHODS A comprehensive literature research was conducted in PubMed, Web of Science and Embase databases to identify case-control and cohort studies published up to March 15, 2022 in English. We included studies investigating associations of food and beverage items (excluding alcohol), food groups, dietary patterns, and dietary habits with incidence risk of four main chronic liver diseases involved in the NAFLD-to-HCC progression (i.e., NAFLD, liver fibrosis, liver cirrhosis, and HCC). Three researchers independently performed the literature search, selected eligible articles, performed data abstraction and evaluated study quality. After evaluating adequacy and credibility of the associations reported for each dietary factor and each liver disease outcome, we summarized and evaluated the consistency of associations based on a priori determined criteria considering study design and the proportion of significant associations. RESULTS There were 109 studies included in this review (47 on NAFLD, 1 on liver fibrosis, 6 on liver cirrhosis, and 55 on HCC). Consistent evidence suggested that higher dietary inflammatory potential was associated with increased risk of both NAFLD and HCC whereas Mediterranean diet was associated with lower risk of both diseases. Additionally, greater conformity to the Healthy Eating Index, Dietary Approaches to Stop Hypertension score, and Mediterranean Diet Score, and dietary patterns with high dietary antioxidant capacity reduced NAFLD risk. Some specific foods including soft drinks and red and/or processed meat were associated with increased NAFLD risk while total vegetables and spinach were associated with reduced NAFLD risk. Coffee and white meat consumption were inversely related to HCC risk. CONCLUSIONS Dietary patterns or individual foods representing a more anti-inflammatory potential were associated with reduced risk of both NAFLD and HCC, which implied diet-induced inflammation may impact NAFLD progression towards HCC.
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Affiliation(s)
- Jiali Zheng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, No.227 South Chongqing Road, Rm 415, China
| | - Longgang Zhao
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, USA
| | - Jingwen Dong
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, No.227 South Chongqing Road, Rm 415, China
| | - Huiyi Chen
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, No.227 South Chongqing Road, Rm 415, China
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
| | - Manal M Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Susan E Steck
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, USA
| | - Xiaoguang Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, No.227 South Chongqing Road, Rm 415, China.
| | - Yong-Bing Xiang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, No. 25, Lane 2200, Xie Tu Road, China.
| | - Hui Wang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, No.227 South Chongqing Road, Rm 415, China.
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24
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Zunica ERM, Heintz EC, Axelrod CL, Kirwan JP. Obesity Management in the Primary Prevention of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14164051. [PMID: 36011044 PMCID: PMC9406638 DOI: 10.3390/cancers14164051] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/16/2022] [Accepted: 08/20/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associations between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal.
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Affiliation(s)
| | | | | | - John P. Kirwan
- Correspondence: (C.L.A.); (J.P.K.); Tel.: +1-225-763-2513 (J.P.K.)
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25
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Yokoyama E, Takeda T, Watanabe Z, Iwama N, Satoh M, Murakami T, Sakurai K, Shiga N, Tatsuta N, Saito M, Tachibana M, Arima T, Kuriyama S, Metoki H, Yaegashi N. Association of fish intake with menstrual pain: A cross-sectional study of the Japan Environment and Children’s Study. PLoS One 2022; 17:e0269042. [PMID: 35862448 PMCID: PMC9302766 DOI: 10.1371/journal.pone.0269042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 05/13/2022] [Indexed: 11/18/2022] Open
Abstract
The relationship between fish eating habits and menstrual pain is unknown. Elucidating this relationship can inform dietary guidance for reproductive age women with menstrual pain. The aim of this study was to clarify the relationship between fish intake frequency/preference and menstrual pain. This cross-sectional study was conducted at the Miyagi Regional Center as an adjunct study of the Japan Environment and Children’s Study, and 2060 eligible women (mean age, 31.9 years) participated. Fish intake frequency (“< 1 time/week,” “1 time/week,” “2–3 times/week,” or “≥ 4 times/week”), preference (“like,” “neutral,” or “dislike”), and menstrual pain (no/mild or moderate-to-severe) were assessed at 1.5 years after the last delivery through self-administered questionnaires. The association between fish intake frequency/preference and prevalence of moderate-to-severe menstrual pain was evaluated through logistic regression analyses. Our results show that, compared with the “< 1 time/week” (38.0%) group, the “1 time/week” (26.9%), “2–3 times/week” (27.8%), and “≥ 4 times/week” (23.9%) groups showed a lower prevalence of moderate-to-severe menstrual pain (p < 0.01). The prevalence of moderate-to-severe menstrual pain was 27.7%, 27.6%, and 34.4% in the “like,” “neutral,” and “dislike” groups, respectively. Multivariate logistic regression showed that frequent fish intake was associated with a lower prevalence of moderate-to-severe menstrual pain (“1 time/week”: odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.41–0.86, “2–3 times/week”: OR = 0.64; 95% CI, 0.45–0.90 and “≥ 4 times/week”: OR = 0.52; 95% CI, 0.34–0.80; trend p = 0.004). Multivariate logistic regression showed no association between fish preference and moderate-to-severe menstrual pain (“dislike” vs “like”: OR = 1.16; 95% CI, 0.78–1.73). There was a significant negative association between fish intake frequency and menstrual pain. It is suggested that fish intake can reduce or prevent menstrual pain.
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Affiliation(s)
- Emi Yokoyama
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takashi Takeda
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Division of Women’s Health, Research Institute of Traditional Asian Medicine, Kindai University, Osaka-Sayama, Osaka, Japan
- * E-mail:
| | - Zen Watanabe
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Noriyuki Iwama
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
| | - Michihiro Satoh
- Division of Public Health, Hygiene and epidemiology, Tohoku Medical and Pharmaceutical University Faculty of Medicine, Sendai, Miyagi, Japan
| | - Takahisa Murakami
- Division of Public Health, Hygiene and epidemiology, Tohoku Medical and Pharmaceutical University Faculty of Medicine, Sendai, Miyagi, Japan
| | - Kasumi Sakurai
- Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Naomi Shiga
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Nozomi Tatsuta
- Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masatoshi Saito
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Department of Maternal and Fetal Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masahito Tachibana
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takahiro Arima
- Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Shinichi Kuriyama
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
- Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hirohito Metoki
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
- Division of Public Health, Hygiene and epidemiology, Tohoku Medical and Pharmaceutical University Faculty of Medicine, Sendai, Miyagi, Japan
| | - Nobuo Yaegashi
- Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
- Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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26
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Yu J, Liu Z, Liang D, Li J, Ma S, Wang G, Chen W. Meat Intake and the Risk of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies. Nutr Cancer 2022; 74:3340-3350. [PMID: 35583453 DOI: 10.1080/01635581.2022.2077386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The association between meat intake and hepatocellular carcinoma (HCC) risk is still unclear. We conducted a meta-analysis with observational studies to clarify this relationship. A total of 17 studies involving 2,915,680 participants and 4,953 cases of HCC were included in the meta-analysis. Ten studies reported red meat intake, nine reported white meat intake, nine reported fish intake, seven reported processed meat intake, and five reported total meat intake. The results showed that the consumption of red meat (relative risk [RR] = 1.04; 95% confidence interval [CI]: 0.91-1.18; I2=50.50%; P = 0.033) and total meat intake (RR = 1.01; 95% CI: 0.90-1.13; I2 = 15.50%; P = 0.316) were not associated with risk of HCC. However, a higher dietary intake of processed meat (RR = 1.20; 95% CI: 1.02-1.41; I2 = 26.30%; P = 0.228) may increase the risk of HCC. In contrast, the intake of white meat (RR = 0.76; 95% CI: 0.63-0.92; I2 = 68.30%; P = 0.001) and fish (RR = 0.91; 95% CI: 0.86-0.96; I2 =40.90%; P = 0.095) were inversely associated with risk of HCC. Our findings suggest that dietary intervention may be an effective approach to preventing HCC. These need to be verified with further well-designed observational studies and experimental clinical research.
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Affiliation(s)
- Jinchuan Yu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Zhengxiang Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Di Liang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Jiujiu Li
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Shaodi Ma
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Guangjun Wang
- School of Public Health, Anhui Medical University, Hefei, China
| | - Wenjun Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
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27
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Jiang W, Li FR, Yang HH, Chen GC, Hua YF. Relationship Between Fish Oil Use and Incidence of Primary Liver Cancer: Findings From a Population-Based Prospective Cohort Study. Front Nutr 2022; 8:771984. [PMID: 35036409 PMCID: PMC8759152 DOI: 10.3389/fnut.2021.771984] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/24/2021] [Indexed: 12/13/2022] Open
Abstract
Background: N-3 long-chain polyunsaturated fatty acids (LCPUFAs) prevented non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in studies of mouse models. We examined prospective relationships between fish oil use and risk of primary liver cancer and the major histological subtypes, such as HCC and intrahepatic cholangiocarcinoma (ICC). Methods: We included 434,584 middle-aged and older men and women who were free of cancer at recruitment of the UK Biobank (2006–2010). Information on fish oil use and other dietary habits was collected via questionnaires. Cox proportional hazards models were used to compute the hazard ratio (HR) and 95% CI of liver cancer associated with fish oil use, with adjustment for socio-demographic, lifestyle, dietary, and other clinical risk factors. Results: At baseline, 31.4% of participants reported regular use of fish oil supplements. During a median of 7.8 years of follow-up, 262 incident liver cancer cases were identified, among which 127 were HCC and 110 were ICC cases. As compared with non-users, fish oil users had a significantly 44% (95% CI: 25–59%) lower risk of total liver cancer, and 52% (95% CI: 24–70%) and 40% (95% CI: 7–61%) lower risk of HCC and ICC, respectively. Higher intake of oily fish also was associated with a lower risk of HCC (≥2 vs. <1 serving/week: HR = 0.46; 95% CI: 0.23–0.96; P-trend = 0.027) but not ICC (P-trend = 0.96). Conclusion: Habitual use of fish oil supplements was associated lower risk of primary liver cancer regardless of cancer histological subtypes, potentially supporting a beneficial role of dietary n-3 LCPUFAs in liver cancer prevention.
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Affiliation(s)
- Wei Jiang
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Fu-Rong Li
- School of Medicine, Southern University of Science and Technology, Shenzhen, China.,Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Huan-Huan Yang
- Wanke School of Public Health, Tsinghua University, Beijing, China
| | - Guo-Chong Chen
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Yong-Fei Hua
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
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28
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Stratifying individuals into non-alcoholic fatty liver disease risk levels using time series machine learning models. J Biomed Inform 2022; 126:103986. [PMID: 35007752 DOI: 10.1016/j.jbi.2022.103986] [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: 08/31/2021] [Revised: 12/01/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population worldwide, and its prevalence is anticipated to increase globally. While most NAFLD patients are asymptomatic, NAFLD may progress to fibrosis, cirrhosis, cardiovascular disease, and diabetes. Research reports, with daunting results, show the challenge that NAFLD's burden causes to global population health. The current process for identifying fibrosis risk levels is inefficient, expensive, does not cover all potential populations, and does not identify the risk in time. Instead of invasive liver biopsies, we implemented a non-invasive fibrosis assessment process calculated from clinical data (accessed via EMRs/EHRs). We stratified patients' risks for fibrosis from 2007 to 2017 by modeling the risk in 5579 individuals. The process involved time-series machine learning models (Hidden Markov Models and Group-Based Trajectory Models) profiled fibrosis risk by modeling patients' latent medical status resulted in three groups. The high-risk group had abnormal lab test values and a higher prevalence of chronic conditions. This study can help overcome the inefficient, traditional process of detecting fibrosis via biopsies (that are also medically unfeasible due to their invasive nature, the medical resources involved, and costs) at early stages. Thus longitudinal risk assessment may be used to make population-specific medical recommendations targeting early detection of high risk patients, to avoid the development of fibrosis disease and its complications as well as decrease healthcare costs.
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Stephen NM, Maradagi T, Kavalappa YP, Sharma H, Ponesakki G. Seafood nutraceuticals: Health benefits and functional properties. RESEARCH AND TECHNOLOGICAL ADVANCES IN FOOD SCIENCE 2022:109-139. [DOI: 10.1016/b978-0-12-824369-5.00012-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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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: 19] [Impact Index Per Article: 4.8] [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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Nie Z, Chen M, Gao Y, Huang D, Cao H, Peng Y, Guo N, Zhang S. Regulated Cell Death in Urinary Malignancies. Front Cell Dev Biol 2021; 9:789004. [PMID: 34869390 PMCID: PMC8633115 DOI: 10.3389/fcell.2021.789004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/25/2021] [Indexed: 12/14/2022] Open
Abstract
Urinary malignancies refer to a series of malignant tumors that occur in the urinary system and mainly include kidney, bladder, and prostate cancers. Although local or systemic radiotherapy and chemotherapy, immunotherapy, castration therapy and other methods have been applied to treat these diseases, their high recurrence and metastasis rate remain problems for patients. With in-depth research on the pathogenesis of urinary malignant tumors, this work suggests that regulatory cell death (RCD) plays an important role in their occurrence and development. These RCD pathways are stimulated by various internal and external environmental factors and can induce cell death or permit cell survival under the control of various signal molecules, thereby affecting tumor progression or therapeutic efficacy. Among the previously reported RCD methods, necroptosis, pyroptosis, ferroptosis, and neutrophil extracellular traps (NETs) have attracted research attention. These modes transmit death signals through signal molecules, such as cysteine-aspartic proteases (caspase) family and tumor necrosis factor-α (TNF-α) that have a wide and profound influence on tumor proliferation or death and even change the sensitivity of tumor cells to therapy. This review discussed the effects of necroptosis, pyroptosis, ferroptosis, and NETs on kidney, bladder and prostate cancer and summarized the latest research and achievements in these fields. Future directions and possibility of improving the denouement of urinary system tumors treatment by targeting RCD therapy were also explored.
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Affiliation(s)
- Zhenyu Nie
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
| | - Mei Chen
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
| | - Yuanhui Gao
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
| | - Denggao Huang
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
| | - Hui Cao
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
| | - Yanling Peng
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
| | - Na Guo
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
| | - Shufang Zhang
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
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Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC. Biomedicines 2021; 9:1524. [PMID: 34829753 PMCID: PMC8614742 DOI: 10.3390/biomedicines9111524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients' health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Silvia Fargion
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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Ruiz-Margáin A, Román-Calleja BM, Moreno-Guillén P, González-Regueiro JA, Kúsulas-Delint D, Campos-Murguía A, Flores-García NC, Macías-Rodríguez RU. Nutritional therapy for hepatocellular carcinoma. World J Gastrointest Oncol 2021; 13:1440-1452. [PMID: 34721776 PMCID: PMC8529929 DOI: 10.4251/wjgo.v13.i10.1440] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/23/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and presents together with cirrhosis in most cases. In addition to commonly recognized risk factors for HCC development, such as hepatitis B virus/hepatitis C virus infection, age and alcohol/tobacco consumption, there are nutritional risk factors also related to HCC development including high intake of saturated fats derived from red meat, type of cooking (generation of heterocyclic amines) and contamination of foods with aflatoxins. On the contrary, protective nutritional factors include diets rich in fiber, fruits and vegetables, n-3 polyunsaturated fatty acids and coffee. While the patient is being evaluated for staging and treatment of HCC, special attention should be paid to nutritional support, including proper nutritional assessment and therapy by a multidisciplinary team. It must be considered that these patients usually develop HCC on top of long-lasting cirrhosis, and therefore they could present with severe malnutrition. Cirrhosis-related complications should be properly addressed and considered for nutritional care. In addition to traditional methods, functional testing, phase angle and computed tomography scan derived skeletal muscle index-L3 are among the most useful tools for nutritional assessment. Nutritional therapy should be centered on providing enough energy and protein to manage the increased requirements of both cirrhosis and cancer. Supplementation with branched-chain amino acids is also recommended as it improves response to treatment, nutritional status and survival, and finally physical exercise must be encouraged and adapted to individual needs.
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Affiliation(s)
- Astrid Ruiz-Margáin
- Liver Nutrition Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
- Liver Fibrosis and Nutrition Lab, MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases- Research Network), Mexico City 14080, Mexico
| | - Berenice M Román-Calleja
- Liver Nutrition Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Paulina Moreno-Guillén
- Liver Nutrition Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - José A González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Deyanira Kúsulas-Delint
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Alejandro Campos-Murguía
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Nayelli C Flores-García
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Ricardo Ulises Macías-Rodríguez
- Liver Fibrosis and Nutrition Lab, MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases- Research Network), Mexico City 14080, Mexico
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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Moussa I, Day RS, Li R, Kaseb A, Jalal PK, Daniel‐MacDougall C, Hatia RI, Abdelhakeem A, Rashid A, Chun YS, Li D, Hassan MM. Association of dietary fat intake and hepatocellular carcinoma among US adults. Cancer Med 2021; 10:7308-7319. [PMID: 34535983 PMCID: PMC8525131 DOI: 10.1002/cam4.4256] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 08/05/2021] [Accepted: 08/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The role of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) remains unclear. We investigated the associations of total fat and fatty acids with risk of HCC among US adults in a hospital-based case-control study. METHODS We analyzed data from 641 cases and 1034 controls recruited at MD Anderson Cancer Center during 2001-2018. Cases were new patients with a pathologically or radiologically confirmed diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck. Cases and controls were frequency-matched by age and sex. Dietary intake was assessed using a validated food frequency questionnaire. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. RESULTS Monounsaturated fatty acid (MUFA) intake was inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.49; 95% CI, 0.33-0.72). Total polyunsaturated fatty acid (PUFA) intake was directly associated with HCC risk (highest vs. lowest tertile: OR, 1.82; 95% CI, 1.23-2.70). Omega-6 PUFA was directly associated with HCC risk (highest vs. lowest tertile: OR 2.29; 95% CI, 1.52-3.44). Long-chain omega-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) intake was also inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.50; 95% CI, 0.33-0.70). No association was observed for saturated fat and HCC risk. CONCLUSION Our findings support a direct association of omega-6 PUFA intake with HCC and an inverse association of MUFA and long-chain omega-3 PUFA intake with HCC.
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Affiliation(s)
- Iman Moussa
- Department of Epidemiology, Human Genetics, and Environmental ScienceSchool of Public HealthThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Rena S. Day
- Division of Epidemiology, Human Genetics, & Environmental SciencesSouthwest Center for Occupational and Environmental HealthMichael & Susan Dell Center for Healthy LivingSchool of Public HealthThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Ruosha Li
- Department of Biostatistics and Data ScienceSchool of Public HealthThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Prasun K. Jalal
- Division of Gastroenterology and HepatologyDepartment of MedicineBaylor College of MedicineHoustonTexasUSA
| | | | - Rikita I. Hatia
- Department of EpidemiologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Ahmed Abdelhakeem
- Department of Internal MedicineBaptist Hospitals of Southeast TexasBeaumontTexasUSA
| | - Asif Rashid
- Department of PathologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Yun Shin Chun
- Division of SurgeryDepartment of Surgical OncologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Donghui Li
- Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Manal M. Hassan
- Department of EpidemiologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
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Francque SM, Marchesini G, Kautz A, Walmsley M, Dorner R, Lazarus JV, Zelber-Sagi S, Hallsworth K, Busetto L, Frühbeck G, Dicker D, Woodward E, Korenjak M, Willemse J, Koek GH, Vinker S, Ungan M, Mendive JM, Lionis C. Non-alcoholic fatty liver disease: A patient guideline. JHEP Rep 2021; 3:100322. [PMID: 34693236 PMCID: PMC8514420 DOI: 10.1016/j.jhepr.2021.100322] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 06/08/2021] [Indexed: 02/07/2023] Open
Abstract
This patient guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent chronic liver disease worldwide and comes with a high disease burden. Yet, there is a lot of unawareness. Furthermore, many aspects of the disease are still to be unravelled, which has an important impact on the information that is given (or not) to patients. Its management requires a close interaction between patients and their many healthcare providers. It is important for patients to develop a full understanding of NAFLD in order to enable them to take an active role in their disease management. This guide summarises the current knowledge relevant to NAFLD and its management. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations, intended to support patients in making informed decisions.
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Key Words
- ALD, alcohol-related or alcoholic liver disease
- ASH, alcoholic steatohepatitis
- BMI, body mass index
- CAP, controlled attenuation parameter
- CT, computed tomography
- CVD, cardiovascular disease
- EASD, European Association for the Study of Diabetes
- EASL, European Association for the Study of the Liver
- EASO, European Association for the Study of Obesity
- FIB-4, fibrosis-4 index
- FXR, farnesoid X receptor
- GLP-1 RAs, glucagon-like receptor 1 agonists
- GP, general practitioner
- HCC, hepatocellular carcinoma
- HDL, high-density lipoprotein
- LDL, low-density lipoproteins
- MRE, magnetic resonance elastography
- MRI, magnetic resonance imaging
- NAFL, non-alcoholic fatty liver
- NAFLD, non-alcoholic fatty liver disease
- NASH CRN, NASH Clinical Research Network
- NASH, non-alcoholic steatohepatitis
- NIT, non-invasive test
- SMART, specific, measurable, achievable, relevant, timely
- T1D, type 1 diabetes
- T2D, type 2 diabetes
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Affiliation(s)
- Sven M. Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics (LEMP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- InflaMed Centre of Excellence, University of Antwerp, Antwerp, Belgium
- Translational Sciences in Inflammation and Immunology, University of Antwerp, Antwerp, Belgium
| | - Giulio Marchesini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
- Department of Medical and Surgical Sciences, “Alma Mater” University, Bologna, Italy
| | | | | | | | - Jeffrey V. Lazarus
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Spain
| | - Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
- Department of Gastroenterology and Hepatology, The Tel-Aviv Medical Center, Tel-Aviv, Israel
| | - Kate Hallsworth
- Newcastle NIHR Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Luca Busetto
- Department of Medicine, University of Padova, Italy
- European Association for the Study of Obesity
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, University of Navarra Clinic, IdiSNA, CIBEROBN, Pamplona, Spain
- European Association for the Study of Obesity
| | - Dror Dicker
- Department of Internal Medicine, Rabin Medical Center Hasharon Hospital, Tikva, Israel
- European Association for the Study of Obesity
| | | | | | | | - Gerardus H. Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Shlomo Vinker
- Department of Family Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- World Organization of Family Doctors (WONCA)
- European General Practice Research Network (EGPRN)
- Israel Association of Family Physicians, Israel
- Leumit Health Services, Tel Aviv, Israel
| | | | - Juan M. Mendive
- Training Unit of Family Medicine, Catalan Institute of Health, Barcelona, Spain
- European Society for Primary Care Gastroenterology
| | - Christos Lionis
- European Society for Primary Care Gastroenterology
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Greece
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Adherence to a Fish-Rich Dietary Pattern Is Associated with Chronic Hepatitis C Patients Showing Low Viral Load: Implications for Nutritional Management. Nutrients 2021; 13:nu13103337. [PMID: 34684338 PMCID: PMC8541240 DOI: 10.3390/nu13103337] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 01/04/2023] Open
Abstract
Hepatitis C virus (HCV) infection is influenced by genetic (e.g., APOE polymorphisms) and environmental factors between the virus and the host. HCV modulates the host’s lipid metabolism but dietary components influence lipids and in vitro HCV RNA replication. Few data exist on the role of dietary features or patterns (DPs) in HCV infection. Herein, we aimed to evaluate the nutritional profiles of chronic HCV (CHC) and spontaneous clearance (SC) Mexican patients in the context of APOE alleles and their correlation with HCV-related variables. The fibrosis-related APOEε3 allele prevailed in CHC and SC patients, who had four DPs (“meat and soft drinks”, DP1; “processed animal and fried foods”, DP2; “Mexican-healthy”, DP3; and “fish-rich”, DP4). In CHC subjects, polyunsaturated fatty acid intake (PUFA ≥ 4.9%) was negatively associated, and fiber intake (≥21.5 g/day) was positively associated with a high viral load (p < 0.036). High adherence to fish-rich DP4 was associated with a higher frequency of CHC individuals consuming PUFA ≥ 4.9% (p = 0.004) and low viral load (p = 0.036), but a lower frequency of CHC individuals consuming fiber ≥21.5 g/day (p = 0.038). In SC and CHC individuals, modifying unhealthy DPs and targeting HCV-interacting nutrients, respectively, could be part of a nutritional management strategy to prevent further liver damage.
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Liao H, Shi J, Wen K, Lin J, Liu Q, Shi B, Yan Y, Xiao Z. Molecular Targets of Ferroptosis in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:985-996. [PMID: 34466409 PMCID: PMC8403010 DOI: 10.2147/jhc.s325593] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/11/2021] [Indexed: 12/14/2022] Open
Abstract
Ferroptosis is a special form of regulatory cell death caused by the accumulation of intracellular iron and lipid peroxidation. Here, we summarize the research progress on ferroptosis in hepatocellular carcinoma (HCC), trace the development of the concept of ferroptosis and its key regulatory factors, and discuss the application value of ferroptosis in the treatment of HCC from different perspectives. We believe that exploring the relationship between ferroptosis and HCC and clarifying the metabolism and expression of ferroptosis-specific genes and molecules will accelerate the development of novel ferroptosis-related molecules as HCC markers and therapeutic targets. We hope to provide a theoretical basis for better diagnosis and treatment to effectively improve the prognosis of patients with HCC.
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Affiliation(s)
- Hao Liao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Juanyi Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Kai Wen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Jianhong Lin
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Qinghua Liu
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Bingchao Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yongcong Yan
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
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Jiao J, Kwan SY, Sabotta CM, Tanaka H, Veillon L, Warmoes MO, Lorenzi PL, Wang Y, Wei P, Hawk ET, Almeda JL, McCormick JB, Fisher-Hoch SP, Beretta L. Circulating Fatty Acids Associated with Advanced Liver Fibrosis and Hepatocellular Carcinoma in South Texas Hispanics. Cancer Epidemiol Biomarkers Prev 2021; 30:1643-1651. [PMID: 34155064 PMCID: PMC8419070 DOI: 10.1158/1055-9965.epi-21-0183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/23/2021] [Accepted: 05/27/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND Hispanics in South Texas have high rates of hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Liver fibrosis severity is the strongest predictive factor of NAFLD progression to HCC. We examined the association between free fatty acids (FA) and advanced liver fibrosis or HCC in this population. METHODS We quantified 45 FAs in plasma of 116 subjects of the Cameron County Hispanic Cohort, 15 Hispanics with HCC, and 56 first/second-degree relatives of Hispanics with HCC. Liver fibrosis was assessed by FibroScan. RESULTS Advanced liver fibrosis was significantly associated with low expression of very long chain (VLC) saturated FAs (SFA), odd chain SFAs, and VLC n-3 polyunsaturated FAs [PUFA; AOR; 95% confidence interval (CI), 10.4 (3.7-29.6); P < 0.001; 5.7 (2.2-15.2); P < 0.001; and 3.7 (1.5-9.3); P = 0.005]. VLC n3-PUFAs significantly improved the performance of the noninvasive markers for advanced fibrosis - APRI, FIB-4, and NFS. Plasma concentrations of VLC SFAs and VLC n-3 PUFAs were further reduced in patients with HCC. Low concentrations of these FAs were also observed in relatives of patients with HCC and in subjects with the PNPLA3 rs738409 homozygous genotype. CONCLUSIONS Low plasma concentrations of VLC n-3 PUFAs and VLC SFAs were strongly associated with advanced liver fibrosis and HCC in this population. Genetic factors were associated with low concentrations of these FAs as well. IMPACT These results have implications in identifying those at risk for liver fibrosis progression to HCC and in screening this population for advanced fibrosis. They also prompt the evaluation of VLC n-3 PUFA or VLC SFA supplementation to prevent cirrhosis and HCC.
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Suet-Ying Kwan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Caroline M Sabotta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Honami Tanaka
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lucas Veillon
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Marc O Warmoes
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Philip L Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ying Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peng Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ernest T Hawk
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jose Luis Almeda
- Doctors Hospital at Renaissance and University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas
| | - Joseph B McCormick
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas
| | - Susan P Fisher-Hoch
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zelber-Sagi S. Dietary Treatment for NAFLD: New Clinical and Epidemiological Evidence and Updated Recommendations. Semin Liver Dis 2021; 41:248-262. [PMID: 34139786 DOI: 10.1055/s-0041-1729971] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The key factor in preventing and treating nonalcoholic fatty liver disease (NAFLD) is a holistic lifestyle modification approach, encompassing diet based on healthy eating patterns of unprocessed foods, exercise, balanced drinking, and smoking habits. The Mediterranean diet and other healthy dietary patterns can reduce liver fat and may be related with lower disease progression. The type of diet should be tailored to the patient's cultural and personal preferences. Changing dietary composition without reducing caloric intake may offer an additional and sometimes more feasible alternative, so that the nutritional treatment incorporates, but is not focused on, weight reduction goals. The growing global consumption of ultra-processed foods, which is the polar opposite of the Mediterranean diet and its concept of home-based cooking, poses a great challenge in the prevention of NAFLD and probably hepatocellular carcinoma.This review will cover the most updated clinical and epidemiological evidence for lifestyle treatment in NAFLD and provide practical treatment tools.
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Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
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40
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Tan K, Zhang H, Li S, Ma H, Zheng H. Lipid nutritional quality of marine and freshwater bivalves and their aquaculture potential. Crit Rev Food Sci Nutr 2021; 62:6990-7014. [PMID: 33847542 DOI: 10.1080/10408398.2021.1909531] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Omega-3 Long-chain polyunsaturated fatty acids (n-3 LC-PUFA) are beneficial to human health. Since the industrial revolution, with the tremendous increase of human population, the supply of natural n-3 LC-PUFA is far lower than the nutritional need of n-3 LC-PUFA. Therefore, a new alternative source of natural n-3 LC-PUFA is urgently needed to reduce the supply and demand gap of n-3 LC-PUFA. Mollusks, mainly bivalves, are rich in n-3 LC-PUFA, but the information of bivalves' lipid profile is not well organized. Therefore, this study aims to analyze the published fatty acid profiles of bivalves and reveal the potential of bivalve aquaculture in meeting the nutritional needs of human for n-3 LC-PUFA. There are growing evidence show that the nutritional quality of bivalve lipid is not only species-specific, but also geographical specific. To date, bivalve aquaculture has not been evenly practiced across the globe. It can be seen that aquaculture is predominant in Asia, especially China. Unlike fish aquaculture, bivalve aquaculture does not rely on fishmeal and fish oil inputs, so it has better room for expansion. In order to unleash the full potential of bivalve aquaculture, there are some challenges need to be addressed, including recurrent mass mortalities of farmed bivalves, food safety and food security issues. The information of this article is very useful to provide an overview of lipid nutritional quality of bivalves, and reveal the potential of bivalve aquaculture in meeting the growing demand of human for n-3 LC-PUFA.
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Affiliation(s)
- Karsoon Tan
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, China.,Mariculture Research Center for Subtropical Shellfish & Algae of Guangdong Province, Shantou, China.,STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Hongkuan Zhang
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, China.,Mariculture Research Center for Subtropical Shellfish & Algae of Guangdong Province, Shantou, China.,STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Shengkang Li
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, China.,Mariculture Research Center for Subtropical Shellfish & Algae of Guangdong Province, Shantou, China.,STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Hongyu Ma
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, China.,Mariculture Research Center for Subtropical Shellfish & Algae of Guangdong Province, Shantou, China.,STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Huaiping Zheng
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, China.,Mariculture Research Center for Subtropical Shellfish & Algae of Guangdong Province, Shantou, China.,STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
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Dietary Fats, Serum Cholesterol and Liver Cancer Risk: A Systematic Review and Meta-Analysis of Prospective Studies. Cancers (Basel) 2021; 13:cancers13071580. [PMID: 33808094 PMCID: PMC8037522 DOI: 10.3390/cancers13071580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/17/2021] [Accepted: 03/23/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Due to the rapid increase of primary liver cancer incidence and the poor prognosis, it is imperative to identify new modifiable factors such as diet and nutrition for the prevention of liver cancer. Diet high in saturated fatty acids (SFA) has been hypothesized to be associated with increased risk of cancers. However, the associations between dietary fatty acids and liver cancer are not consistent. We aimed to examine the association between dietary total fat, its major components, serum cholesterol, and risk of liver cancer combining current evidence from prospective studies. Our meta-analyses provided new evidence on associations between dietary fats, serum cholesterol, and liver cancer risk. Higher intake of dietary SFA was associated with higher risk of liver cancer while higher serum levels of cholesterol and high-density lipoprotein (HDL) were associated with a lower risk of liver cancer with high between-studies variability. Based on our findings, reducing dietary SFA may help to prevent the development of liver cancer. Abstract To quantify the associations between dietary fats and their major components, as well as serum levels of cholesterol, and liver cancer risk, we performed a systematic review and meta-analysis of prospective studies. We searched PubMed, Embase, and Web of Science up to October 2020 for prospective studies that reported the risk estimates of dietary fats and serum cholesterol for liver cancer risk. We carried out highest versus lowest intake or level and dose-response analyses. Higher intake of dietary saturated fatty acids (SFA) was associated with a higher liver cancer risk in both category analysis (relative risk [RR]highest vs. lowest intake = 1.34, 95% confidence interval [CI]: 1.06, 1.69) and dose-response analysis (RR1% energy = 1.04, 95%CI: 1.01, 1.07). Higher serum total cholesterol was inversely associated with liver cancer but with large between-studies variability (RR1 mmol/L = 0.72, 95%CI: 0.69, 0.75, I2 = 75.3%). The inverse association was more pronounced for serum high-density lipoprotein (HDL) cholesterol (RR1 mmol/L = 0.42, 95%CI: 0.27, 0.64). Higher intake of dietary SFA was associated with higher risk of liver cancer while higher serum levels of cholesterol and HDL were associated with a lower risk of liver cancer with high between-studies variability.
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Khan IM, Gjuka D, Jiao J, Song X, Wang Y, Wang J, Wei P, El-Serag HB, Marrero JA, Beretta L. A Novel Biomarker Panel for the Early Detection and Risk Assessment of Hepatocellular Carcinoma in Patients with Cirrhosis. Cancer Prev Res (Phila) 2021; 14:667-674. [PMID: 33685927 DOI: 10.1158/1940-6207.capr-20-0600] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/01/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022]
Abstract
Novel biomarkers for hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis are urgently needed. We previously identified osteopontin (OPN) as a promising biomarker for the early detection of HCC. This study is to further validate the performance of OPN and identify fatty acids (FA) that could improve OPN's performance in HCC risk assessment in patients with cirrhosis. To that end, we selected 103 patients with cirrhosis under surveillance. Among them, 40 patients developed HCC during follow-up. We investigated in these 103 patients, the association between HCC incidence and prediagnostic serum levels of AFP, OPN, and 46 FAs. OPN performance was higher than AFP in detecting prediagnosis HCCs and the combination with AFP further improved OPN's performance. For patients with a diagnosis of HCC within 18 months of follow-up (HCC < 18 months), AUC for OPN + AFP was 0.77. Abundance of 11 FAs [four long-chain saturated FAs (SFA), four n-3 poly-unsaturated FAs (PUFA), and three n-6 PUFAs] were statistically different between patients who developed HCC and those who did not. Abundance changes correlated with time to diagnosis for the PUFAs, but not for the SFAs. Adding arachidic acid (20:0) and n-3 docosapentaenoic acid (22:5n3) to OPN and AFP improved the discriminatory performance (AUC = 0.83). AUC for this panel reached 0.87 for HCC < 18 months (82% sensitivity at 81% specificity). In conclusion, we identified a panel of 4 markers with strong performances that could have significant utility in HCC early detection in patients with cirrhosis under surveillance. PREVENTION RELEVANCE: This study identified a panel of 4 biomarkers that identifies with high performance patients with cirrhosis at high risk for HCC. This panel could have utility in HCC early detection in patients with cirrhosis under surveillance.
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Affiliation(s)
- Ilvira M Khan
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Donjeta Gjuka
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jingjing Jiao
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaoling Song
- Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ying Wang
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peng Wei
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hashem B El-Serag
- Department of Medicine, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Jorge A Marrero
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
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Ji XW, Wang J, Shen QM, Li ZY, Jiang YF, Liu DK, Tan YT, Li HL, Xiang YB. Dietary fat intake and liver cancer incidence: A population-based cohort study in Chinese men. Int J Cancer 2021; 148:2982-2996. [PMID: 33559177 DOI: 10.1002/ijc.33507] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/31/2021] [Accepted: 02/02/2021] [Indexed: 02/06/2023]
Abstract
To date, limited studies have focused on the association between dietary fat and liver cancer risk, especially in China. Our study aims to evaluate the association between dietary fat intake and liver cancer incidence risk in men. Dietary fat intake was obtained through a validated food frequency questionnaire in a Chinese prospective cohort. The Cox regression model was utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). After exclusion, 59 998 recruitments were finally analyzed with a total follow-up time of 714 339 person-years, 431 incident liver cancer cases were newly identified among them. The adjusted HRs (95% CIs) for the highest vs lowest quartile of total fat, saturated fat, monounsaturated fat (MUFA), and polyunsaturated fat (PUFA) were 1.33 (1.01-1.75), 1.50 (1.13-1.97), 1.26 (0.96-1.65), and 1.41 (1.07-1.86), and the corresponding P-trend values were .008, .005, .034, and .005, respectively. In the secondary analysis among participants tested for hepatitis B virus, we found that higher intakes of saturated fat and PUFA were also associated with increased liver cancer risks. Besides, high risks of per standard deviation alterations of the total fat, saturated fat and MUFA were detected in liver cancer, and these results were similar to those concluded from the full-cohort analysis. In conclusion, dietary intakes of total fat, saturated fat, PUFA, and probably MUFA might increase liver cancer risks. Our study provides suggestive advice to public administration on dietary suggestions, and related measures taken from managing dietary fat intake might reduce liver cancer incidence.
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Affiliation(s)
- Xiao-Wei Ji
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jing Wang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Qiu-Ming Shen
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zhuo-Ying Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yu-Fei Jiang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Da-Ke Liu
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yu-Ting Tan
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Hong-Lan Li
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yong-Bing Xiang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Wang C, Wei X, Shao G. Functional Doxorubicin-Loaded Omega-3 Unsaturated Fatty Acids Nanoparticles in Reversing Hepatocellular Carcinoma Multidrug Resistance. Med Sci Monit 2021; 27:e927727. [PMID: 33524008 PMCID: PMC7863563 DOI: 10.12659/msm.927727] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Background This study investigated a nanoparticle drug delivery system to reverse multidrug resistance (MDR) and assessed its anticancer efficacy in hepatocellular carcinoma (HCC). Material/Methods Docosahexaenoic acid (DHA) was used as the functional excipient and doxorubicin (DOX) as the chemotherapeutic drug to synthesize DOX nanoparticles (DOX-nano). The human HCC cell line HepG2 was used for experiments. HepG2/DOX, HepG2+DOX, HepG2+DOX-nano, HepG2/DOX+DOX, and HepG2/DOX+DOX-nano groups cells were treated with DOX or DOX-nano (5 μg/mL). Nude mice bearing a HepG2/DOX xenograft were divided into model, DOX, vector-nano, and DOX-nano groups and injected with saline, DOX reagent, vector-nano, and DOX-nano (2 mg/kg), respectively. Next, cytotoxicity, cellular uptake, cell apoptosis and migration, fluorescence imaging, TUNEL assay, and tumor inhibition effects were assessed in vitro and in vivo. Furthermore, expression of MDR-related proteins was also detected using western blotting. Results Fluorescence imaging showed that the DOX uptake in the DOX-nano-treated group was the strongest in the HCC cells or tumors. Cell apoptosis was significantly increased in DOX-nano-treated HepG2/DOX cells and tumors, and cell migration was significantly inhibited in the DOX-nano-treated HepG2/DOX cells compared with the other groups. The tumor inhibitory rate in DOX-nano-injected tumors was also significantly higher than in other groups. The expression of breast cancer resistance protein, B-cell lymphoma 2, lung resistance protein, multidrug resistance protein, and protein kinase C alpha was significantly decreased in DOX-nano-treated HepG2/DOX cells and xenograft tumors. Significantly better antitumor and MDR-reversing effects were also observed in the HepG2+DOX group compared with the HepG2/DOX group. Conclusions This study revealed the potential efficacy of a DOX-nano drug delivery system for the treatment of HCC, using HepG2/DOX cells and nude mice bearing HepG2/DOX xenografts.
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Affiliation(s)
- Chunlei Wang
- Pharmaceutical Preparation Section, Cancer Hospital of The University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China (mainland).,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China (mainland)
| | - Xiaoyan Wei
- Pharmaceutical Preparation Section, Cancer Hospital of The University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China (mainland).,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China (mainland)
| | - Guoliang Shao
- Pharmaceutical Preparation Section, Cancer Hospital of The University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China (mainland).,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China (mainland)
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Kusnik A, Hunter N, Rasbach E, Miethke T, Reissfelder C, Ebert MP, Teufel A. Co-Medication and Nutrition in Hepatocellular Carcinoma: Potentially Preventative Strategies in Hepatocellular Carcinoma. Dig Dis 2021; 39:526-533. [PMID: 33429390 DOI: 10.1159/000514277] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/11/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with about 841,000 new cases and 782,000 deaths annually. Given the clearly defined population at risk, mostly patients with liver cirrhosis, prevention of HCC could be highly effective. SUMMARY Besides regular ultrasound surveillance, numerous publications have suggested protective effects of diverse drugs and nutrients. However, none of those preventive options has made it into clinical routine or practice guidelines. We therefore summarize the current status of preventive effects of drugs such as statins, acetylsalicylic acid (ASA), and metformin, but also dietary aspects and nutrients such as coffee, tea, and vitamin D supplementation. A successful implementation of some of these strategies may potentially lead to improved prevention of HCC development in patients with liver cirrhosis. Key Messages: Accumulating data suggest that particularly ASA, antidiabetic therapies, and statins may substantially decrease HCC incidence in patients at risk.
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Affiliation(s)
- Alexander Kusnik
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nicole Hunter
- Institute of Medical Microbiology and Hygiene, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Erik Rasbach
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Thomas Miethke
- Institute of Medical Microbiology and Hygiene, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Reissfelder
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias Philip Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Li S, Saviano A, Erstad DJ, Hoshida Y, Fuchs BC, Baumert T, Tanabe KK. Risk Factors, Pathogenesis, and Strategies for Hepatocellular Carcinoma Prevention: Emphasis on Secondary Prevention and Its Translational Challenges. J Clin Med 2020; 9:E3817. [PMID: 33255794 PMCID: PMC7760293 DOI: 10.3390/jcm9123817] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/11/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality globally. Given the limited therapeutic efficacy in advanced HCC, prevention of HCC carcinogenesis could serve as an effective strategy. Patients with chronic fibrosis due to viral or metabolic etiologies are at a high risk of developing HCC. Primary prevention seeks to eliminate cancer predisposing risk factors while tertiary prevention aims to prevent HCC recurrence. Secondary prevention targets patients with baseline chronic liver disease. Various epidemiological and experimental studies have identified candidates for secondary prevention-both etiology-specific and generic prevention strategies-including statins, aspirin, and anti-diabetic drugs. The introduction of multi-cell based omics analysis along with better characterization of the hepatic microenvironment will further facilitate the identification of targets for prevention. In this review, we will summarize HCC risk factors, pathogenesis, and discuss strategies of HCC prevention. We will focus on secondary prevention and also discuss current challenges in translating experimental work into clinical practice.
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Affiliation(s)
- Shen Li
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Antonio Saviano
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Derek J. Erstad
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Yujin Hoshida
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Department of Internal Medicine, Dallas, TX 75390, USA;
| | - Bryan C. Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Thomas Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Kenneth K. Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
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Assessing the safety of transarterial locoregional delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat liver. Eur J Pharm Biopharm 2020; 158:273-283. [PMID: 33242579 DOI: 10.1016/j.ejpb.2020.10.018] [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: 04/24/2020] [Revised: 09/14/2020] [Accepted: 10/25/2020] [Indexed: 11/22/2022]
Abstract
Hepatic-arterial infusion (HAI) of low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) (LDL-DHA) has been shown in a rat hepatoma model to be a promising treatment for hepatocellular carcinoma. To date, little is known regarding the safety of HAI of LDL-DHA to the liver. Therefore, we aimed to investigate the deposition, metabolism and safety of HAI of LDL-DHA (2, 4 or 8 mg/kg) in the rat. Following HAI, fluorescent labeled LDL nanoparticles displayed a biexponential plasma concentration time curve as the particles were rapidly extracted by the liver. Overall, increasing doses of HAI of LDL-DHA was well tolerated in the rat. Body weight, plasma biochemistry and histology were all unremarkable and molecular markers of inflammation did not increase with treatment. Lipidomics analyses showed that LDL-DHA was preferentially oxidized to the anti-inflammatory mediator, protectin DX. We conclude that HAI of LDL-DHA nanoparticles is not only safe, but provides potential hepatoprotective benefits.
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Mouillot T, Rizk M, Pais de Barros JP, Gilloteau A, Busson A, Bernard-Chabert B, Thiefin G, Barraud H, Bronowicki JP, Richou C, Di Martino V, Doffoel M, Minello A, Latournerie M, Jouve JL, Brondel L, Brindisi MC, Petit JM, Hillon P, Cottet V. Fatty acid composition of the erythrocyte membrane and risk of hepatocellular carcinoma in cirrhotic patients. Aliment Pharmacol Ther 2020; 52:1503-1515. [PMID: 32780481 DOI: 10.1111/apt.16022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/05/2020] [Accepted: 07/16/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Disturbances in fatty acid (FA) metabolism have been reported in cirrhosis, but the role of FAs in the development of hepatocellular carcinoma (HCC) is still unclear. Biomarkers are a promising means to explore the associations between exogenous intake or endogenous production of FAs and cancer risk. AIM To estimate the relationship between fatty acid content in erythrocyte membranes and HCC risk in cirrhotic patients METHODS: The "CiRCE" case-control study recruited cirrhotic patients from six French hospitals between 2008 and 2012. Cases were cirrhotic patients with HCC (n = 349); controls were cirrhotic patients without HCC at inclusion (n = 550). FA composition of phospholipids in erythrocyte membranes was determined by high performance gas chromatography. Odds ratios for HCC risk according to FA concentrations were estimated with multivariable logistic regression. RESULTS HCC patients were older and more often men (P < 0.001). In both groups, saturated FAs represented more than 39% of all FAs in erythrocyte membranes, mono-unsaturated FAs around 14%, and polyunsaturated FAs around 46%. High levels of C15:0 + C17:0, C20:1 n-9, C18:2 n-6 and C20:2 n-6 were associated with higher risk of HCC. The levels of C18:0 and C20:4 n-6 were lower in HCC cases than in controls. CONCLUSIONS The FA composition of erythrocyte membranes differed according to the presence of HCC with higher levels of saturated FAs, linoleic and eicosadienoic acids, and lower levels of stearic and arachidonic acids. These alterations may reflect particular dietary patterns and/or altered FA metabolism. Further investigations are warranted.
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Diao P, Wang X, Jia F, Kimura T, Hu X, Shirotori S, Nakamura I, Sato Y, Nakayama J, Moriya K, Koike K, Gonzalez FJ, Aoyama T, Tanaka N. A saturated fatty acid-rich diet enhances hepatic lipogenesis and tumorigenesis in HCV core gene transgenic mice. J Nutr Biochem 2020; 85:108460. [PMID: 32992072 PMCID: PMC7756930 DOI: 10.1016/j.jnutbio.2020.108460] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 05/25/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023]
Abstract
Previous studies suggested that high consumption of saturated fatty acid (SFA) is a risk factor for liver cancer. However, it remains unclear how dietary SFA affects liver tumorigenesis. This study aimed to investigate the impact of a SFA-rich diet on hepatic tumorigenesis using hepatitis C virus core gene transgenic (HCVcpTg) mice that spontaneously developed hepatic steatosis and tumors with aging. Male HCVcpTg mice were treated for 15 months with a purified control diet or SFA-rich diet prepared by replacing soybean oil in the control diet with hydrogenated coconut oil, and phenotypic changes were assessed. In this special diet, almost all dietary fatty acids were SFA. Long-term feeding of SFA-rich diet to HCVcpTg mice increased hepatic steatosis, liver dysfunction, and the prevalence of liver tumors, likely due to stimulation of de novo lipogenesis, activation of the pro-inflammatory and pro-oncogenic transcription factor nuclear factor-kappa B (NF-κB), enhanced c-Jun N-terminal kinase/activator protein 1 (JNK/AP-1) signaling and induction of the oncogenes cyclin D1 and p62/sequestosome 1. The SFA-rich diet did not affect liver fibrosis or autophagy. Collectively, long-term SFA-rich diet consumption promoted hepatic tumorigenesis mainly through activation of lipogenesis, NF-κB, and JNK/AP-1 signaling. We therefore propose that HCV-infected patients should avoid excessive intake of SFA-rich foods to prevent liver cancer.
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Affiliation(s)
- Pan Diao
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Xiaojing Wang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Department of Gastroenterology, Lishui Hospital, Zhejiang University School of Medicine, Lishui, Zhejiang, People's Republic of China
| | - Fangping Jia
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Xiao Hu
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Department of Pathophysiology, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Saki Shirotori
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ibuki Nakamura
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yoshiko Sato
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Jun Nakayama
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kyoji Moriya
- Department of Infection Control and Prevention, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Toshifumi Aoyama
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Research Center for Social Systems, Shinshu University, Matsumoto, Japan.
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50
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Simon TG, Chan AT. Lifestyle and Environmental Approaches for the Primary Prevention of Hepatocellular Carcinoma. Clin Liver Dis 2020; 24:549-576. [PMID: 33012445 PMCID: PMC7536356 DOI: 10.1016/j.cld.2020.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Patients with chronic liver disease are at increased risk of developing hepatocellular carcinoma (HCC). Most patients diagnosed with HCC have limited treatment options and a poor overall prognosis, with a 5-year survival less than 15%. Preventing the development of HCC represents the most important strategy. However, current guidelines lack specific recommendations for primary prevention. Lifestyle factors may be central in the pathogenesis of HCC, and primary prevention strategies focused on lifestyle modification could represent an important approach to the prevention of HCC. Both experimental and epidemiologic studies have identified promising chemopreventive agents for the primary prevention of HCC.
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Affiliation(s)
- Tracey G. Simon
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - Andrew T. Chan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA,Broad Institute, Boston MA,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston MA
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