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The Role of Dietary Bioactive Compounds on Liver Cancer and Non-alcoholic Fatty Liver Disease

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Phytochemicals and Human Health".

Deadline for manuscript submissions: closed (25 September 2023) | Viewed by 19222

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Dr. Ben Chi-bun Ko

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State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
Interests: natural products; target identification; hepatocellular carcinoma; drug discovery; metabolism; gene regulation; lysosomes

Special Issue Information

Dear Colleagues,

Dietary bioactive compounds are extranutritional constituents that typically occur in small quantities in foods. There are being intensively studied to evaluate their effects on health.

Dietary bioactive compounds exert beneficial effects on several metabolic disorders associated with the liver. Natural products and related phytochemicals act through multiple pathways, such as modulating gut microbiota, improving redox stress, and anti-inflammation.

Globally, liver cancer is a kind of frequent fatal malignancy. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Several pharmacological interventions, chemotherapy and immunotherapy, have been approved for use in its treatment. Nevertheless, they have been found to display a variety of negative side effects. On the other hand, prevalence of non-alcoholic fatty liver disease (NAFLD) has risen rapidly and is now a frequent cause of chronic liver disease and HCC. Dietary bioactive compounds that alleviate NAFLD could reduce the risk of HCC development.

This Special Issue provides a platform for researchers to discuss the role of dietary bioactive compounds on liver cancer and NAFLD with the aim of helping to promote the development of this field. In the present Special Issue, we welcome original articles, narrative and systematic reviews.

Dr. Ben Chi-bun Ko
Guest Editor

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Keywords

dietary bioactive compounds
phytochemicals
natural products
hepatocellular carcinoma
HCC
liver cancer
non-alcoholic fatty liver disease
NAFLD
inflammation
redox stress
nutrition

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Published Papers (6 papers)

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Research

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17 pages, 1931 KiB

Open AccessArticle

PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids

by Milla-Maria Tauriainen, Susanne Csader, Maria Lankinen, Kwun Kwan Lo, Congjia Chen, Olli Lahtinen, Hani El-Nezamy, Markku Laakso and Ursula Schwab

Nutrients 2024, 16(2), 261; https://doi.org/10.3390/nu16020261 - 16 Jan 2024

Viewed by 2397

Abstract

The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m²) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA. Full article

(This article belongs to the Special Issue The Role of Dietary Bioactive Compounds on Liver Cancer and Non-alcoholic Fatty Liver Disease)

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18 pages, 12188 KiB

Open AccessArticle

Furanocoumarin Notopterol: Inhibition of Hepatocellular Carcinogenesis through Suppression of Cancer Stemness Signaling and Induction of Oxidative Stress-Associated Cell Death

by Ting-Yun Huang, Ching-Kuo Yang, Ming-Yao Chen, Vijesh Kumar Yadav, Iat-Hang Fong, Chi-Tai Yeh and Yih-Giun Cherng

Nutrients 2023, 15(11), 2447; https://doi.org/10.3390/nu15112447 - 24 May 2023

Cited by 10 | Viewed by 2920

Abstract

Background: Hepatocellular carcinoma (HCC) remains an aggressive malignancy with a poor prognosis and a leading cause of cancer-related mortality globally. Cumulative evidence suggests critical roles for endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in chronic liver diseases. However, the role of ER stress in HCC pathogenesis, aggressiveness and therapy response remains unclear and understudied. Objectives: Against this background, the present study evaluated the therapeutic efficacy and feasibility of notopterol (NOT), a furanocoumarin and principal component of Notopterygium incisum, in the modulation of ER stress and cancer stemness, and the subsequent effect on liver oncogenicity. Methods: An array of biomolecular methods including Western blot, drug cytotoxicity, cell motility, immunofluorescence, colony and tumorsphere formation, flow-cytometric mitochondrial function, GSH/GSSG ratio, and tumor xenograft ex vivo assays were used in the study. Results: Herein, we demonstrated that NOT significantly suppresses the viability, migration, and invasion capacity of the human HCC HepJ5 and Mahlavu cell lines by disrupting ATF4 expression, inhibiting JAK2 activation, and downregulating the GPX1 and SOD1 expression in vitro. NOT also markedly suppressed the expression of vimentin (VIM), snail, b-catenin, and N-cadherin in the HCC cells, dose-dependently. Treatment with NOT significantly attenuated cancer stem cells (CSCs)-like phenotypes, namely colony and tumorsphere formation, with the concomitant downregulation of stemness markers OCT4, SOX2, CD133, and upregulated PARP-1 cleavage, dose-dependently. We also demonstrated that NOT anticancer activity was strongly associated with increased cellular reactive oxidative stress (ROS) but, conversely, reduced mitochondrial membrane potential and function in the HepJ5 and Mahlavu cells in vitro. Our tumor xenograft studies showed that compared with sorafenib, NOT elicited greater tumor growth suppression without adverse changes in mice body weights. Compared with the untreated control and sorafenib-treated mice, NOT-treated mice exhibited markedly greater apoptosis ex vivo, and this was associated with the co-suppression of stemness and drug-resistance markers OCT4, SOX2, ALDH1, and the upregulation of endoplasmic reticulum stress and oxidative stress factors PERK and CHOP. Conclusions: In summary, we demonstrated for the first time that NOT exhibits strong anticancer activity via the suppression of cancer stemness, enhanced endoplasmic reticulum stress and increased oxidative stress thus projecting NOT as a potentially effective therapeutic agent against HCC. Full article

(This article belongs to the Special Issue The Role of Dietary Bioactive Compounds on Liver Cancer and Non-alcoholic Fatty Liver Disease)

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17 pages, 4253 KiB

Open AccessArticle

Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes

by Sin-Hyoung Hong, Yeonhee Hong, Minji Lee, Byeong-Rak Keum and Gun-Hwa Kim

Nutrients 2023, 15(6), 1490; https://doi.org/10.3390/nu15061490 - 20 Mar 2023

Cited by 13 | Viewed by 3036

Abstract

Skatole (3-methylindole, 3MI) is a natural-origin compound derived from plants, insects, and microbial metabolites in human intestines. Skatole has an anti-lipid peroxidation effect and is a biomarker for several diseases. However, its effect on hepatocyte lipid metabolism and lipotoxicity has not been elucidated. Hepatic lipotoxicity is induced by excess saturated free fatty acids in hyperlipidemia, which directly damages the hepatocytes. Lipotoxicity is involved in several metabolic diseases and hepatocytes, particularly affecting nonalcoholic fatty liver disease (NAFLD) progression. NAFLD is caused by the accumulation of fat by excessive free fatty acids (FFAs) in the blood and is accompanied by hepatic damage, such as endoplasmic reticulum (ER) stress, abnormal glucose and insulin metabolism, oxidative stress, and lipoapoptosis with lipid accumulation. Hepatic lipotoxicity causes multiple hepatic damages in NAFLD and has a directly effect on the progression from NAFLD to nonalcoholic steatohepatitis (NASH). This study confirmed that the natural compound skatole improves various damages to hepatocytes caused by lipotoxicity in hyperlipidemic conditions. To induce lipotoxicity, we exposed HepG2, SNU-449, and Huh7 cells to palmitic acid, a saturated fatty acid, and confirmed the protective effect of skatole. Skatole inhibited fat accumulation in the hepatocytes, reduced ER and oxidative stress, and recovered insulin resistance and glucose uptake. Importantly, skatole reduced lipoapoptosis by regulating caspase activity. In conclusion, skatole ameliorated multiple types of hepatocyte damage induced by lipotoxicity in the presence of excess free fatty acids. Full article

(This article belongs to the Special Issue The Role of Dietary Bioactive Compounds on Liver Cancer and Non-alcoholic Fatty Liver Disease)

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15 pages, 2292 KiB

Open AccessArticle

Brassica oleracea Var italica by-Products Prevent Lipid Accumulation and Cell Death in a Liver Cell Model of Lipid Toxicity

by José P. Castelão-Baptista, Sara A. Valente, Sara Canário, David Oppolzer, Ana Barros, Carlos Venâncio, Tânia Martins, Luís Antunes, Vilma A. Sardão, Eduardo Rosa and Paulo J. Oliveira

Nutrients 2023, 15(4), 924; https://doi.org/10.3390/nu15040924 - 12 Feb 2023

Cited by 1 | Viewed by 2726

Abstract

Obesity, a rising concern in the Eastern world, encompasses several co-morbidities, namely non-alcoholic fatty liver disease (NAFLD). Potential natural-based interventions to decrease the burden of obesity complications are being investigated. Many of the edible parts of plants are not sold for consumption and end up as massive waste, losing nutritional potential. In fact, a sizeable amount of waste is generated within the different steps of the food supply chain, representing a massive loss of both plant material and natural resources. A good example is Brassica by-products (BBPs). The objective of this work was to investigate the effect of three different extracts from broccoli (Brassica oleracea var italica) by-products in an in vitro model of free fatty acid (FFA)-induced lipotoxicity using human hepatoma HepG2 cells. Broccoli leaf, stalk, and inflorescence extracts induced a dose-dependent decrease in the cell viability of HepG2 cells. However, the maximal non-lethal concentrations of leaves, stalks, and inflorescences (10 μg/mL) did not compromise mitochondrial function or neutral lipid accumulation in HepG2 cells. The extracts significantly decreased FFA-induced lipid accumulation in HepG2 cells either in a co-incubation or pre-incubation strategy. The broccoli extracts’ capacity to prevent the FFA-induced decrease in catalase activity in HepG2 may explain the observed effects. Full article

(This article belongs to the Special Issue The Role of Dietary Bioactive Compounds on Liver Cancer and Non-alcoholic Fatty Liver Disease)

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Review

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12 pages, 761 KiB

Open AccessReview

A Review of the Effects of Fucoxanthin on NAFLD

by Nor Hafiza Sayuti, Khairul Najmi Muhammad Nawawi, Jo Aan Goon, Norfilza Mohd Mokhtar, Suzana Makpol and Jen Kit Tan

Nutrients 2023, 15(8), 1954; https://doi.org/10.3390/nu15081954 - 19 Apr 2023

Cited by 11 | Viewed by 3181

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease. Fucoxanthin, a red-orange marine carotenoid, is found in natural marine seaweeds with high antioxidant activity and several other remarkable biological features. The aim of this review is to gather evidence of the positive benefits of fucoxanthin on NAFLD. Fucoxanthin provides an extensive list of physiological and biological properties, such as hepatoprotective, anti-obesity, anti-tumor, and anti-diabetes properties, in addition to antioxidant and anti-inflammatory properties. This review focuses on published research on the preventative effects of fucoxanthin on NAFLD from the perspective of human clinical trials, animal experiments in vivo, and in vitro cell investigations. Using a variety of experimental designs, including treatment dosage, experiment model, and experimental periods, the positive effects of fucoxanthin were demonstrated. Fucoxanthin’s biological activities were outlined, with an emphasis on its therapeutic efficacy in NAFLD. Fucoxanthin showed beneficial effects in modulating lipid metabolism, lipogenesis, fatty acid oxidation, adipogenesis, and oxidative stress on NAFLD. A deeper comprehension of NAFLD pathogenesis is essential for the development of novel and effective therapeutic strategies. Full article

(This article belongs to the Special Issue The Role of Dietary Bioactive Compounds on Liver Cancer and Non-alcoholic Fatty Liver Disease)

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Other

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20 pages, 6661 KiB

Open AccessSystematic Review

The Efficacy of Panax ginseng for the Treatment of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Preclinical Studies

by Keungmo Yang, Hee-Hoon Kim, Young-Ri Shim and Myeong Jun Song

Nutrients 2023, 15(3), 721; https://doi.org/10.3390/nu15030721 - 31 Jan 2023

Cited by 7 | Viewed by 3925

Abstract

Although tremendous research has reported the protective effects of natural compounds in nonalcoholic fatty liver disease (NAFLD), there is still no approved drug. This study aimed to examine the efficacy of Panax ginseng in NAFLD in preclinical studies. A total of 41 studies were identified by searching the PubMed, Web of Science, and Cochrane Library databases. The methodological quality was assessed by the risk of bias tool from the Systematic Review Center for Laboratory Animal Experimentation. The standardized mean difference (SMD) with a 95% confidence interval was calculated, and the random effects model was used to examine overall efficacy or heterogeneity. The publication bias was analyzed by Egger’s test. The results showed that Panax ginseng treatment significantly reduced the systemic levels of alanine aminotransferase (SMD: −2.15 IU/L; p < 0.0001), aspartate aminotransferase (SMD: −2.86 IU/L; p < 0.0001), triglyceride (SMD: −2.86 mg/dL; p < 0.0001), total cholesterol (SMD: −1.69 mg/dL; p < 0.0001), low-density lipoprotein (SMD: −1.46 mg/dL; p < 0.0001), and fasting glucose (SMD: −1.45 mg/dL; p < 0.0001) while increasing high-density lipoprotein (SMD: 1.22 mg/dL; p = 0.0002) in NAFLD regardless of animal models or species. These findings may suggest that Panax ginseng is a promising therapeutic agent for NAFLD treatment. Full article

(This article belongs to the Special Issue The Role of Dietary Bioactive Compounds on Liver Cancer and Non-alcoholic Fatty Liver Disease)

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