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Diagnosis and management of fatty liver

Tan PO, Mustaffa N, Tan SS, Lee YY

J R Coll Physicians Edinb, 2020 Sep;50(3):256-261.
PMID: 32936098 DOI: 10.4997/JRCPE.2020.308

Globally, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly and constitutes a significant healthcare burden due to associated complications including hepatic (cirrhosis and hepatocellular cancer) and non-hepatic (cardiovascular deaths) disorders. It is closely linked to insulin resistance and metabolic syndrome but moderate alcohol consumption frequently coexists. Recently, genetic polymorphisms were implicated in the development of non-obese NAFLD. Apart from liver biopsy, in order to assess for steatosis, fibrosis and non-alcoholic steatohepatitis (NASH), advances in non-invasive serum tests and elastography have provided similarly accurate, more accessible and safer alternatives for risk stratification. As for treatment in 2020, weight loss and lifestyle modification remain the central strategy. Unfortunately, no pharmacological agents have been approved thus far, but there are a number of potential therapies in the pipeline for fibrosis and NASH. Treatment of underlying metabolic disorders is important. While the term NAFLD was coined in the 1980s, more recent understanding may support a change in nomenclature highlighting its strong metabolic roots.

Matched MeSH terms: Liver Neoplasms
Fulltext Preparation, antioxidant potential and angiotensin converting enzyme (ACE) inhibitory activity of gum arabic-stabilised magnesium orotate nanoparticles

Abdelkader Hassani, Siti Aslina Hussain?, Abdullah, N., Suryani Kamarudin, Rozita Rosli

International Food Research Journal, 2020;27(1):150-159.
MyJurnal

The present work investigated the antioxidant properties and antihypertensive activity of
magnesium orotate (MgOr) using various established in vitro assays, such as β-carotene
bleaching activity, 1,1-diphenyl-2-picrylhydrazyl (DPPH), and nitric oxide scavenging activity as well as angiotensin converting enzyme (ACE) inhibitory activity. Magnesium orotate
nanoparticles (MgOrGANPs) were prepared using the gum arabic (GA) as stabiliser coatings
for nanoparticles through freeze-drying method. The in vitro cytoxicity of MgOrGANPs
against human breast cancer MCF7, liver cancer HepG2, and colon cancer HT29 was investigated. The nitric oxide (NO) and DPPH scavenging assays of MgOrGANPs showed a
dose-dependent trend, while 500 and 200 µL/mL were significantly more effective than the
other concentrations with an IC50 of 89.56 µg/mL and 63.22% DPPH scavenging capacity
respectively. The exposure of human cancer cells to MgOrGANPs at 1.56 – 1,000 µg/mL
using 3-)4,5-dimethylthiazol-2-yl(2,5-diphenyl tetrazolium bromide (MTT) inhibited the
growth of cell lines examined in a dose-dependent manner. Hence, MgOrGANPs may have
great potential to be applied for cancer treatments.

Matched MeSH terms: Liver Neoplasms
Fulltext Thymoquinone, as a Novel Therapeutic Candidate of Cancers

Almajali B, Al-Jamal HAN, Taib WRW, Ismail I, Johan MF, Doolaanea AA, et al.

Pharmaceuticals (Basel), 2021 Apr 16;14(4).
PMID: 33923474 DOI: 10.3390/ph14040369

To date, natural products are widely used as pharmaceutical agents for many human diseases and cancers. One of the most popular natural products that have been studied for anticancer properties is thymoquinone (TQ). As a bioactive compound of Nigella sativa, TQ has shown anticancer activities through the inhibition of cell proliferation, migration, and invasion. The anticancer efficacy of TQ is being investigated in several human cancers such as pancreatic cancer, breast cancer, colon cancer, hepatic cancer, cervical cancer, and leukemia. Even though TQ induces apoptosis by regulating the expression of pro- apoptotic and anti-apoptotic genes in many cancers, the TQ effect mechanism on such cancers is not yet fully understood. Therefore, the present review has highlighted the TQ effect mechanisms on several signaling pathways and expression of tumor suppressor genes (TSG). Data from relevant published experimental articles on TQ from 2015 to June 2020 were selected by using Google Scholar and PubMed search engines. The present study investigated the effectiveness of TQ alone or in combination with other anticancer therapeutic agents, such as tyrosine kinase inhibitors on cancers, as a future anticancer therapy nominee by using nanotechnology.

Matched MeSH terms: Liver Neoplasms
Fulltext Antioxidant properties and antiproliferative effect of brewers’ rice extract (temukut) on selected cancer cell lines

Tan, B.L., Suhaniza, H.J., Lai, C. C., Norazalina, S., Roselina, K., Norhaizan, M.E.

International Food Research Journal, 2013;20(5):2117-2124.
MyJurnal

Temukut, or brewers’ rice, is a mixture of broken rice, rice bran, and rice germ. Extensive studies have been conducted on rice bran, which possesses various health benefits. Temukut, however has been less well studied. The present study aimed to investigate the antioxidant and growth inhibition properties of temukut extract using colon cancer (HT-29), ovary cancer (Caov-3), and liver cancer (HepG2) cell lines. The antioxidant activity was determined by the β-carotene bleaching assay, analysis of the DPPH radical scavenging capacity, and a FRAP assay. The total phenolic compounds, oryzanol, vitamin E, and phytic acid levels in temukut were also investigated. The antiproliferative activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. There was a significant difference in the cytotoxicity of two types of temukut extract (water and methanol) for HT-29 and Caov-3 cells (p < 0.05) but not for HepG2 cells. The HepG2 cell line is the least sensitive to temukut, (IC50 = 55.30 μg/mL), whereas the highest sensitivity was observed in Caov-3 cells (IC50 =36.67 μg/mL). No cytotoxic effect of temukut was observed on normal cells (BalBlc3T3). Although the content of the phytochemicals studied (total phenolic compounds, vitamin E, oryzanol, and phytic acid) in temukut was lower than that in rice bran, as has been previously reported, the present study demonstrated temukut’s potential to inhibit the proliferation of HT-29, Caov-3, and HepG2 cells.

Matched MeSH terms: Liver Neoplasms
Fulltext Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection

Kouwaki T, Fukushima Y, Daito T, Sanada T, Yamamoto N, Mifsud EJ, et al.

Front Immunol, 2016;7:335.
PMID: 27630638 DOI: 10.3389/fimmu.2016.00335

The innate immune system is essential for controlling viral infection. Hepatitis B virus (HBV) persistently infects human hepatocytes and causes hepatocellular carcinoma. However, the innate immune response to HBV infection in vivo remains unclear. Using a tree shrew animal model, we showed that HBV infection induced hepatic interferon (IFN)-γ expression during early infection. Our in vitro study demonstrated that hepatic NK cells produced IFN-γ in response to HBV only in the presence of hepatic F4/80(+) cells. Moreover, extracellular vesicles (EVs) released from HBV-infected hepatocytes contained viral nucleic acids and induced NKG2D ligand expression in macrophages by stimulating MyD88, TICAM-1, and MAVS-dependent pathways. In addition, depletion of exosomes from EVs markedly reduced NKG2D ligand expression, suggesting the importance of exosomes for NK cell activation. In contrast, infection of hepatocytes with HBV increased immunoregulatory microRNA levels in EVs and exosomes, which were transferred to macrophages, thereby suppressing IL-12p35 mRNA expression in macrophages to counteract the host innate immune response. IFN-γ increased the hepatic expression of DDX60 and augmented the DDX60-dependent degradation of cytoplasmic HBV RNA. Our results elucidated the crucial role of exosomes in antiviral innate immune response against HBV.

Matched MeSH terms: Liver Neoplasms
Fulltext Hepatitis B infection: what the primary care doctors should know

Kew ST, Loh KY

Malays Fam Physician, 2006;1(1):8-10.
MyJurnal

Hepatitis B virus infection is a global public health problem. The prevalence of hepatitis B infection is higher in Asia. The rate of HBsAg carriage in the general population ranges from 2-20%. The WHO has recommended that by the end of 21st century hepatitis B vaccination should be incorporated into routine childhood immunisation programmes for all nations. Vaccination against hepatitis B remains the most important aspect of preventive care. Most importantly hepatitis B vaccination can protect individual from fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma. Primary care physicians must be familiar with the pathology, epidemiological and clinical presentations of this disease and be able to refer patients for appropriate treatment at the tertiary centre.

Matched MeSH terms: Liver Neoplasms
Fulltext Ginger Extract (Zingiber officinale Roscoe) Triggers Apoptosis in Hepatocarcinogenesis Induced Rats

Yasmin Anum, M.Y., Shahriza, Z.A., Looi, ML, Shafina Hanim, M.H., Harlianshah, H., Noor Aini, A.H., et al.

Medicine & Health, 2008;3(2):263-274.
MyJurnal

Ginger extract has been reported previously by our group to exhibit anticancer and an-tioxidant effects by reducing tumour burden and lipid peroxidation respectively in he-patocarcinogenesis induced rats. The current study examined the expression of pro-apoptotic protein caspase-8 and anti-apoptotic protein Bcl-2 in hepatocarcinogenesis treated rats. Thirty normal male Wistar rats were divided into 5 groups based on the diet given: i) control (normal rat chow), ii) olive oil, iii) ginger extract (100mg/kg body weight), iv) choline deficient diet + ethionine, CDE (to induce liver cancer) and v) CDE+ ginger extract. Rats were killed at week 8, and liver tissues were excised for immuno-histochemical study to identify pro-apoptotic and anti-apoptotic proteins, caspase-8 and Bcl-2. The observation on H&E staining confirmed the CDE diet induced liver can-cer as indicated by the presence of numerous oval cells. Identification of Bcl-2 expres-sion showed that 91.6% (11/12) of the samples from the CDE group revealed positive staining while treatment with ginger extract however inhibited the expression with only 8.4% (1/12) samples showing positive staining for Bcl-2. As for caspase-8 protein, 41.7% (5/12) of the samples from CDE group showed positive staining, which in-creased to 100% (12/12) with ginger extract treatment. Our findings suggest that gin-ger extract has an anticancer effect by inducing apoptosis in liver cancer cells via up-regulation of the expression of pro-apoptotic protein, caspase-8 and down-regulation of the expression of anti-apoptotic protein Bcl-2.

Matched MeSH terms: Liver Neoplasms
Fulltext Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated with Melicope ptelefolia leaf extract reveals transcriptome profiles exhibiting anticancer activity

Kabir MF, Mohd Ali J, Haji Hashim O

PeerJ, 2018;6:e5203.
PMID: 30042885 DOI: 10.7717/peerj.5203

Background: We have previously reported anticancer activities of Melicope ptelefolia (MP) leaf extracts on four different cancer cell lines. However, the underlying mechanisms of actions have yet to be deciphered. In the present study, the anticancer activity of MP hexane extract (MP-HX) on colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines was characterized through microarray gene expression profiling.
Methods: HCT116 and HepG2 cells were treated with MP-HX for 24 hr. Total RNA was extracted from the cells and used for transcriptome profiling using Applied Biosystem GeneChip™ Human Gene 2.0 ST Array. Gene expression data was analysed using an Applied Biosystems Expression Console and Transcriptome Analysis Console software. Pathway enrichment analyses was performed using Ingenuity Pathway Analysis (IPA) software. The microarray data was validated by profiling the expression of 17 genes through quantitative reverse transcription PCR (RT-qPCR).
Results: MP-HX induced differential expression of 1,290 and 1,325 genes in HCT116 and HepG2 cells, respectively (microarray data fold change, MA_FC ≥ ±2.0). The direction of gene expression change for the 17 genes assayed through RT-qPCR agree with the microarray data. In both cell lines, MP-HX modulated the expression of many genes in directions that support antiproliferative activity. IPA software analyses revealed MP-HX modulated canonical pathways, networks and biological processes that are associated with cell cycle, DNA replication, cellular growth and cell proliferation. In both cell lines, upregulation of genes which promote apoptosis, cell cycle arrest and growth inhibition were observed, while genes that are typically overexpressed in diverse human cancers or those that promoted cell cycle progression, DNA replication and cellular proliferation were downregulated. Some of the genes upregulated by MP-HX include pro-apoptotic genes (DDIT3, BBC3, JUN), cell cycle arresting (CDKN1A, CDKN2B), growth arrest/repair (TP53, GADD45A) and metastasis suppression (NDRG1). MP-HX downregulated the expression of genes that could promote anti-apoptotic effect, cell cycle progression, tumor development and progression, which include BIRC5, CCNA2, CCNB1, CCNB2, CCNE2, CDK1/2/6, GINS2, HELLS, MCM2/10 PLK1, RRM2 and SKP2. It is interesting to note that all six top-ranked genes proposed to be cancer-associated (PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2) were downregulated by MP-HX in both cell lines.
Discussion: The present study showed that the anticancer activities of MP-HX are exerted through its actions on genes regulating apoptosis, cell proliferation, DNA replication and cell cycle progression. These findings further project the potential use of MP as a nutraceutical agent for cancer therapeutics.

Matched MeSH terms: Liver Neoplasms
Fulltext Hepatocellular Carcinoma in Malaysia and Its Changing Trend

Raihan R, Azzeri A, H Shabaruddin F, Mohamed R

Euroasian J Hepatogastroenterol, 2018 05 01;8(1):54-56.
PMID: 29963463 DOI: 10.5005/jp-journals-10018-1259

Hepatocellular carcinoma (HCC) is one of the leading causes of death globally. In Malaysia liver cancer is the eighth most common cause of cancer for both gender and fifth most common cause of cancer for males. Liver cancer is a cause of premature death in Malaysia: The trend from 1990 to 2010 was observed upward. Since 1990, the annual years of life lost (YLLs) from liver cancer have increased by 31.5%. Older persons are at higher risk and there is male predominance observed. Curative surgical resection, liver transplantation, and supportive symptomatic care, including percutaneous ethanol injection and radiofrequency ablation (RFA), and noncurative transarterial chemoembolization (TACE) are among available treatment facilities. Yet the survival rate is very poor as majority of patients present at very advanced stage. Hepatitis B virus (HBV) remained the leading cause of HCC in Malaysia. Several studies showed cryptogenic causes, which are mainly nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) among the predominant causes of HCC in Malaysia than hepatitis C virus (HCV), alcohol, or any other reason. This mainly correlates with the increasing incidence of diabetes and obesity in Malaysia. How to cite this article: Raihan R, Azzeri A, Shabaruddin FH, Mohamed R. Hepatocellular Carcinoma in Malaysia and Its Changing Trend. Euroasian J Hepato-Gastroenterol 2018;8(1):54-56.

Matched MeSH terms: Liver Neoplasms
Weight Reduction and Pioglitazone are Cost-Effective for the Treatment of Non-Alcoholic Fatty Liver Disease in Thailand

Chongmelaxme B, Phisalprapa P, Sawangjit R, Dilokthornsakul P, Chaiyakunapruk N

Pharmacoeconomics, 2019 02;37(2):267-278.
PMID: 30430467 DOI: 10.1007/s40273-018-0736-0

INTRODUCTION: This study evaluated lifetime liver-related clinical outcomes, costs of treatment, and the cost-effectiveness of treatment options for non-alcoholic fatty liver disease (NAFLD) in Thailand.
METHODS: A cost-utility analysis using a lifetime Markov model was conducted among Thai patients with NAFLD, from a societal perspective. Pioglitazone, vitamin E, a weight reduction program, and usual care were investigated, with the outcomes of interest being the number of cirrhosis and hepatocellular carcinoma (HCC) cases, life expectancy, quality-adjusted life-years (QALYs), lifetime costs, and the incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed.
RESULTS: When compared with usual care, a weight reduction program can prevent cirrhosis and HCC cases by 13.91% (95% credible interval [CrI] 0.97, 20.59) and 2.12% (95% CrI 0.43, 4.56), respectively; pioglitazone can prevent cirrhosis and HCC cases by 9.30% (95% CrI -2.52, 15.24) and 1.42% (95% CrI -0.18, 3.74), respectively; and vitamin E can prevent cirrhosis and HCC cases by 7.32% (95% CrI -4.64, 15.56) and 1.12% (95% CrI -0.81, 3.44), respectively. Estimated incremental life expectancy and incremental QALYs for all treatment options compared with usual care were approximately 0.06 years and 0.07 QALYs, respectively. The lifetime costs of both a weight reduction program and pioglitazone were less than usual care, while vitamin E was $3050 (95% CrI 2354, 3650). The weight reduction program dominated all other treatment options. The probability of being cost-effective in Thailand's willingness-to-pay threshold ($4546/QALY gained) was 76% for the weight reduction program, 22% for pioglitazone, 2% for usual care, and 0% for vitamin E.
CONCLUSIONS: A weight reduction program can prevent cirrhosis and HCC occurrences, and dominates all other treatment options. Pioglitazone and vitamin E demonstrated a trend towards decreasing the number of cirrhosis and HCC cases.

Matched MeSH terms: Liver Neoplasms
A Case Study on Chronic Hepatitis-C Viral infection Associated with Hepatocellular Carcinoma in a Tertiary Hospital of Bangladesh

Islam MJ, Saha SK, Das AK, Jahan MS, Pervin S, Karim CF, et al.

Mymensingh Med J, 2019 Oct;28(4):935-939.
PMID: 31599264

Hepatocellular carcinoma (HCC) is an important reason of liver-related death globally. HCC is the fifth most common cancer, the third most common cause for cancer related death in the world and responsible for approximately one million deaths each year. The incidence of HCC is expected to increase in the next two decades, largely due to hepatitis C infection and secondary cirrhosis. We have reported a case of hepatocellular carcinoma in a 56-year-old man with peritoneal metastasis. Diagnostic imaging (Ultra sonogram & CT-Scan) shown: a large hypo density, irregular outline lesion noted in right lower liver, post contrast image shown patchy enhancement of the lesion. His serum Alpha-Feto Protein (AFP) level was very high with elevated serum alanine amino transaminase (ALT) enzyme and prothrombin time. Histopathological (microscopic) features are compatible with Hepatocellular carcinoma. His Hepatitis C viral DNA load e.g., core protein variants and genotype 1, have been reported. The patient was treated by surgical resection followed by conservative treatment includes sorafenib & interferon alpha. This case report aims to outlines the epidemiology of HCC in chronic HCV, risk factors and pathophysiology that contribute to this disease process, related pathophysiology of patient's clinical features, screening recommendations, and the available statistics on the impact of new direct-acting antiviral treatment on the development on HCC.

Matched MeSH terms: Liver Neoplasms
Anticholesterol activity of anacardium occidentale linn. Does it involve in reverse cholesterol transport?

Mohd Kamal Nik Hasan, Ihsan Safwan Kamarazaman, Nur Zalikha Mohd Taza, Rasadah Mat Ali, Mohd Shahidan Mohd Arshad, Zamree Md Shah, et al.

Sains Malaysiana, 2015;44:1501-1510.

Anacardium occidentale belongs to the Anacardiaceae family. It had been scientifically proven to have antihypercholesterolemia effect in high cholesterol diet induced animal laboratory study. However there is no study regarding the mechanisms involves in cholesterol reducing effect by A. occidentale leaves extract. In this study, cytotoxic assessment and anti-cholesterol activity of A. occidentale leaves aqueous extract (AOE) were investigated. Cytotoxic study was performed by exposing hepatoma cell (Hep G2) towards AOE with concentration ranging from 0.002 to 20 mg/mL for 24 h. Anacardium occidentale extract was found to be not toxic to the cell. Then, the highest and not toxic AOE concentrations (20, 10, 5 and 2.5 mg/mL) were selected for anti-cholesterol study. The ability of AOE to reduce cholesterol in cell culture experiment was carried out by pretreating Hep G2 with selected concentrations of AOE in 6-well plate before the cell was exposed to low density lipoprotein (LDL). The concentration of farnesyl-diphosphate farnesyltransferase (FDFT1), apolipoprotein A1 (Apo A1), lecithin-cholesterol acyltransferase (LCAT), low density lipoprotein receptor (LDL R), scavenger receptor B1 (SR-B1), ATP binding cassette transporter A1 (ABCA-1) and hepatic lipase (HL) were determined from the 6-well plate media. The results showed that AOE did not significantly increase the concentration of LDLR. However, AOE significantly increased the concentration of FDFT1, APO A1, LCAT, SRB-1, ABCA-1 and HL. The HMGR activity experiment showed that all selected AOE concentrations cannot significantly reduce the HMGR enzyme activity. These findings suggested that AOE may involve in reverse cholesterol transport process to reduce cholesterol metabolism in Hep G2 cell.

Matched MeSH terms: Liver Neoplasms
A gain of function p53 gene mutant promotes growth suppression in human liver cancer cells

Nor Adzimah Johdi, Siti Nurmi Nasir, Rahman Jamal

Sains Malaysiana, 2017;46:1289-1297.

Primary liver cancer is one of the most common cancer in the world with highest cancer mortality rate. The most common type of primary liver cancer is hepatocellular carcinoma (HCC). There are many risk factors for liver cancer and currently available treatments for HCC are largely inadequate. Gene mutation and dysfunction of p53 are common and is recognized as an important molecular event in hepatocarcinogenesis. Therefore, replacement of the aberrant p53 gene is an attractive approach in the treatment of HCC providing an alternative treatment for primary HCC. In this study, we assessed whether the transfection with wild-type p53 gene is able to restore the pro-apoptotic effects and evaluate the feasibility of gene therapy in fixing a faulty p53 molecule. We established a non-viral cationic lipid-based p53 gene delivery into two human HCC cell lines namely HLF and PLC/PRF/5 cells. Both cell lines have mutations in the p53 gene. We compared the results with the normal liver cell line, WRL68, that constitutively expresses the wild-type p53 gene. In this study, the introduction of wild-type p53 gene into HLF and PLC/PRF/5 cells resulted in an increased of p53 gene expression, protein expression and cells growth inhibition shown in MTS reduction cell viability assay, FITC-Annexin V and PI apoptosis assay, western blot and caspase activity assay. In summary, the study provides a promising therapeutic approach for p53 gene delivery into HCC patients. The p53 gene delivery can be instituted together with chemotherapy as a combination treatment to induce apoptosis.

Matched MeSH terms: Liver Neoplasms
Fulltext Genomic analysis of Hepatitis B virus and its association with disease manifestations in Bangladesh

Raihan R, Akbar SMF, Al Mahtab M, Takahashi K, Masumoto J, Tabassum S, et al.

PLoS One, 2019;14(6):e0218744.
PMID: 31251754 DOI: 10.1371/journal.pone.0218744

The direct cytopathic effects of the hepatitis B virus (HBV) on subsequent liver damage are not fully understood in HBV-infected patients. However, associations between the prevalence of various HBV genotypes and the extent of liver damage have been reported from different parts of the world. The purpose of this study was to determine the distribution of HBV genotypes in patients with chronic HBV infection in Bangladesh, a country of 160 million people, of which approximately 3-6 million are chronically infected HBV patients. In addition, whole and partial genome sequencing of HBV was performed to evaluate the relationship between HBV mutations and genotypes. We found that 42% of the patients with low HBV DNA and normal levels of alanine aminotransferase (ALT) had HBV genotype D. In contrast, the HBV genotype C was dominant among patients with high HBV DNA levels (>2000 IU/ml) and elevated ALT and in patients with liver cirrhosis (LC) and hepatocellular carcinomas (HCC). Whole and partial genome sequences of HBV revealed that most patients with LC and HCC had HBV genotype C with mutations at the T1762/A1764 positions. It seems that Bangladesh represents a borderline country, situated within East Asia, which mainly consists of individuals with HBV genotypes B and C, whereas in the western parts of Asia, HBV genotypes A and D are prevalent. Bangladesh is, therefore, an excellent model for the comparison of the pathophysiology of three major HBV genotypes in a single population. The findings of this study suggest a possible association between HBV viral factors and the extent of liver damage in chronic HBV-infected patients.

Matched MeSH terms: Liver Neoplasms
Fulltext Antiproliferative and Apoptotic Effects of Cardamonin against Hepatocellular Carcinoma HepG2 Cells

Badroon NA, Abdul Majid N, Alshawsh MA

Nutrients, 2020 Jun 12;12(6).
PMID: 32545423 DOI: 10.3390/nu12061757

Liver cancer is the sixth most common cancer in terms of incidence and the fourth in terms of mortality. Hepatocellular carcinoma (HCC) represents almost 90% of primary liver cancer and has become a major health problem globally. Cardamonin (CADMN) is a natural bioactive chalcone found in several edible plants such as cardamom and Alpinia species. Previous studies have shown that CADMN possesses anticancer activities against breast, lung, prostate and colorectal cancer. In the present study, the mechanisms underlying the anti-hepatocellular carcinoma effects of CADMN were investigated against HepG2 cells. The results demonstrated that CADMN has anti-proliferative effects and apoptotic action on HepG2 cells. CADMN showed potent cytotoxicity against HepG2 cells with an IC50 of 17.1 ± 0.592 μM at 72 h. Flow cytometry analysis demonstrated that CADMN arrests HepG2 cells in G1 phase and induces a significant increase in early and late apoptosis in a time-dependent manner. The mechanism by which CADMN induces apoptotic action was via activation of both extrinsic and intrinsic pathways. Moreover, the findings of this study showed the involvement of reactive oxygen species (ROS), which inhibit the NF-κB pathway and further enhance the apoptotic process. Together, our findings further support the potential anticancer activity of CADMN as an alternative therapeutic agent against HCC.

Matched MeSH terms: Liver Neoplasms
Fulltext Potential chemoprevention of diethylnitrosamine-initiated and 2-acetylaminofluorene-promoted hepatocarcinogenesis by zerumbone from the rhizomes of the subtropical ginger (Zingiber zerumbet)

Taha MM, Abdul AB, Abdullah R, Ibrahim TA, Abdelwahab SI, Mohan S

Chem Biol Interact, 2010 Aug 05;186(3):295-305.
PMID: 20452335 DOI: 10.1016/j.cbi.2010.04.029

Zerumbone (ZER), a monosesquiterpene found in the subtropical ginger (Zingiber zerumbet Smith), possesses antiproliferative properties to several cancer cells lines, including the cervical, skin and colon cancers. In this study, the antitumourigenic effects of ZER were assessed in rats induced to develop liver cancer with a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and dietary 2-acetylaminofluorene (AAF) (0.02%). The rats also received intraperitoneal ZER injections at 15, 30 or 60 mg/kg body wt. twice a week for 11 weeks, beginning week four post-DEN injection. The hepatocytes of positive control (DEN/AAF) rats were smaller with larger hyperchromatic nuclei than normal, showing cytoplasmic granulation and intracytoplasmic violaceous material, which were characteristics of hepatocarcinogenesis. Histopathological evaluations showed that ZER protects the rat liver from the carcinogenic effects of DEN and AAF. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP) and alpha-fetoprotein (AFP) were significantly lower (P<0.05) in ZER-treated than untreated rats with liver cancer. The liver malondialdehyde (MDA) concentrations significantly (P<0.05) increased in the untreated DEN/AAF rats indicating hepatic lipid peroxidation. There was also significant (P<0.05) reduction in the hepatic tissue glutathione (GSH) concentrations. The liver sections of untreated DEN/AAF rats also showed abundant proliferating cell nuclear antigen (PCNA), while in ZER-treated rats the expression of this antigen was significantly (P<0.05) lowered. By the TUNEL assay, there were significantly (P<0.05) higher numbers of apoptotic cells in DEN/AAF rats treated with ZER than those untreated. Zerumbone treatment had also increased Bax and decreased Bcl-2 protein expression in the livers of DEN/AAF rats, which suggested increased apoptosis. Even after 11 weeks of ZER treatment, there was no evidence of abnormality in the liver of normal rats. This study suggests that ZER reduces oxidative stress, inhibits proliferation, induces mitochondria-regulated apoptosis, thus minimising DEN/AAF-induced carcinogenesis in rat liver. Therefore, ZER has great potential in the treatment of liver cancers.

Matched MeSH terms: Liver Neoplasms/chemically induced; Liver Neoplasms/pathology; Liver Neoplasms/prevention & control*
Fulltext Herbal Formulation C168 Attenuates Proliferation and Induces Apoptosis in HCT 116 Human Colorectal Carcinoma Cells: Role of Oxidative Stress and DNA Damage

Leong LM, Chan KM, Hamid A, Latip J, Rajab NF

Evid Based Complement Alternat Med, 2016;2016:2091085.
PMID: 26884792 DOI: 10.1155/2016/2091085

The use of herbal formulations has gained scientific interest, particularly in cancer treatment. In this study, the herbal formulation of interest, denoted as C168, is a mixture of eight genera of plants. This study aims to investigate the antiproliferative effect of C168 methanol extract (CME) on various cancer cells and its underlying mechanism of action on the most responsive cell line, namely, HCT 116 cells. CME exerted antiproliferative activities on HCT 116 colorectal carcinoma cells and HepG2 hepatocellular carcinoma cells but not on CCD-841-CoN normal colon epithelial cells, Jurkat E6.1 lymphoblastic leukemic cells, and V79-4 Chinese hamster lung fibroblasts. Further investigation on HCT 116 cells showed that CME induced G2/M cell-cycle arrest and apoptosis. Treatment of CME induced oxidative stress in HCT 116 cells by increasing the superoxide anion level and decreasing the intracellular glutathione. CME also increased tail moment value and H2AX phosphorylation in HCT 116 cells, suggesting DNA damage as an early signal of CME induced apoptosis. Loss of mitochondrial membrane potential in CME-treated cells also indicated the involvement of mitochondria in CME induced apoptosis. This study indicated the selectivity of CME toward colon cancer cells with the involvement of oxidative damage as its possible mechanism of action.

Matched MeSH terms: Liver Neoplasms
Fulltext Hepatoblastoma in a low birth weight infant : a case report and review of the literature

Kaur G, Mutum SS

Malays J Med Sci, 2001 Jan;8(1):69-72.
PMID: 22973160

Hepatoblastoma is the most common primary liver tumour of childhood. This is a case report of a one-year-old boy who presented with a one-month history of progressive abdominal distension and weight loss. He was cachexic, anaemic, had gross hepatomegaly and ascites. He had been born prematurely with a birth weight of 1.23 kg, and his developmental milestones were delayed. Ultrasound and CT scan demonstrated a large solid tumour in the left lobe of the liver with a smaller superficial nodule in the right lobe. Serum alpha fetoprotein was significantly raised. A left lobe hepatectomy and complete excision of the right sided nodule was performed. There was no evidence of metastatic disease. Histopathological examination confirmed hepatoblastoma of the fetal type. The patient developed features of intestinal obstruction a few days after surgery and he succumbed ten days after re-laparotomy. The clinical presentation and investigation results in this case are characteristic. Recent reports have suggested a strong relationship between very low birth weight (< 1500gm)/prematurity and hepatoblastoma as is present in this case. Surgery is the mainstay of therapy in hepatoblastoma. A brief review of the literature on this tumour is presented.

Matched MeSH terms: Liver Neoplasms
Liver cirrhosis in Malaysia: peculiar epidemiology in a multiracial Asian country

Qua CS, Goh KL

J Gastroenterol Hepatol, 2011 Aug;26(8):1333-7.
PMID: 21443669 DOI: 10.1111/j.1440-1746.2011.06732.x

To determine the etiology of liver cirrhosis and risk factors for hepatocellular carcinoma (HCC) in a multiracial Asian population.

Matched MeSH terms: Liver Neoplasms/ethnology*
Tumour necrosis factor alpha down-regulates the expression of peroxisome proliferator activated receptor alpha (PPARα) in human hepatocarcinoma HepG2 cells by activation of NF-κB pathway

Lim WS, Ng DL, Kor SB, Wong HK, Tengku-Muhammad TS, Choo QC, et al.

Cytokine, 2013 Jan;61(1):266-74.
PMID: 23141142 DOI: 10.1016/j.cyto.2012.10.007

Peroxisome proliferator activated receptor-alpha (PPARα) plays a major role in the regulation of lipid and glucose homeostasis, and inflammatory responses. The objectives of the study were to systematically investigate the effects of TNF-α and its regulatory pathway on PPARα expression in HepG2 cells using Real-Time RT-PCR and western blot analysis. Here, TNF-α suppressed PPARα mRNA expression in a dose- and time-dependent manner at the level of gene transcription. Pre-treatment of cells with 10μM of Wedelolactone for 2h was sufficient to restore PPARα expression to basal levels and also affected the expression of PPARα-regulated genes. This study also demonstrated that TNF-α represses PPARα expression by augmenting the activity of canonical NF-κB signalling pathway. This was shown by the abrogation of TNF-α-mediated PPARα down-regulation, after both p65 and p50 were knocked down via siRNA. The IKK contributes to IκBα degradation and mediates inducible phosphorylation of p105 at Ser933. Surprisingly, phosphorylation of p65 at Ser468 and Ser536 were severely abrogated with Wedelolactone inhibition, suggesting that Ser468 and Ser536, but not Ser276, may mediate the TNF-α inhibitory action on PPARα gene expression. These results suggest that TNF-α might, at least in part, suppress PPARα expression through activation of IKK/p50/p105/p65 pathway. Furthermore, phosphorylation of p65 at Ser468 and Ser536 may play a crucial role in the mechanism that limits PPARα production in the human HepG2 cells.

Matched MeSH terms: Liver Neoplasms/metabolism

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