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Fulltext Hepatoprotective Effects of Zerumbone against Paracetamol-Induced Acute Hepatotoxicity in Rats

Hamid A, Lee LS, Karim SR, Jufri NF

Malays J Med Sci, 2018 Mar;25(2):64-71.
PMID: 30918456 MyJurnal DOI: 10.21315/mjms2018.25.2.7

Background: Zerumbone (ZER) is a major bioactive compound of Zingiber zerumbet, a wild ginger plant that has been documented to have anti-proliferative, anti-inflammatory and anti-oxidant properties. To investigate its hepatoprotective potential, this study was designed to determine the treatment effects of ZER on acute hepatotoxicity induced by paracetamol (PCM) in rats.
Methods: The control group was administered with phosphate buffer solution (PBS) while the other two groups received PCM alone (1000 mg/kg) and PCM + 25 mg/kg ZER, respectively, at 0 h and 4 h after PCM injection. After 24 h, the blood and liver were collected for differential white blood cell count, liver histological observation and biochemical analysis including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total protein concentration in serum and liver.
Results: Treatment with ZER was found to significantly reduce ALT (P = 0.041), AST (P = 0.044) and total hepatic protein (P = 0.045) in comparison to PCM-induced rats. Rats treated with ZER exhibited the normal structure of hepatocytes with no vacuolisation or necrosis and showed significantly reduced neutrophil count (P = 0.037). This finding suggests its ability to suppress the inflammatory processes caused by PCM overdosage and decrease the hepatocytes tendency to go through necrotic processes.
Conclusion: ZER possessed protective activity against PCM-induced acute hepatotoxicity in a rat model.

Matched MeSH terms: Hepatocytes
Fulltext Palm kernel cake extract exerts hepatoprotective activity in heat-induced oxidative stress in chicken hepatocytes

Oskoueian E, Abdullah N, Idrus Z, Ebrahimi M, Goh YM, Shakeri M, et al.

BMC Complement Altern Med, 2014;14:368.
PMID: 25273634 DOI: 10.1186/1472-6882-14-368

Palm kernel cake (PKC), the most abundant by-product of oil palm industry is believed to contain bioactive compounds with hepatoprotective potential. These compounds may serve as hepatoprotective agents which could help the poultry industry to alleviate adverse effects of heat stress on liver function in chickens.

Matched MeSH terms: Hepatocytes/drug effects*
How does conjugated bilirubin appear in the bloodstream?

Tarmalinggam Y, Prakash ES

Adv Physiol Educ, 2007 Dec;31(4):370-1.
PMID: 18057413
Matched MeSH terms: Hepatocytes/metabolism*
Isothiocyanates and Xenobiotic Detoxification

Abdull Razis AF, Konsue N, Ioannides C

Mol Nutr Food Res, 2018 09;62(18):e1700916.
PMID: 29288567 DOI: 10.1002/mnfr.201700916

The potential of isothiocyanates to antagonize the carcinogenicity of structurally diverse chemicals has been established in animals. A feasible mechanism of action involves protecting DNA by reducing the availability of the genotoxic metabolites of chemical carcinogens by either inhibiting their generation and/or stimulating their detoxification. In vivo as well as in vitro studies conducted in rat/human primary hepatocytes and precision-cut tissue slices have revealed that isothiocyanates can impair cytochrome P450 activity, including the CYP1 family which is the most active in the bioactivation of carcinogens, by virtue of being mechanism-based inactivators. The aromatic phenethyl isothiocyanate is the most effective of those studied, whereas aliphatic isothiocyanates such as sulforaphane and erucin necessitate high doses in order to manifest such effects that may not always be achievable through the diet. In all systems studied, isothiocyanates are strong inducers of detoxification enzyme systems including quinone reductase, glutathione S-transferase, epoxide hydrolase, and UDP-glucuronosyl transferase. Indeed, in smokers phenethyl isothiocyanate intake increases the urinary excretion of inactive mercapturate metabolites of toxic chemicals present in tobacco. Glucosinolates, the precursors of isothiocyanates, have also the potential to upregulate detoxification enzyme systems, but their contribution to the cancer chemoprevention linked to cruciferous vegetable consumption remains to be evaluated.

Matched MeSH terms: Hepatocytes/drug effects
Fulltext Natural Compound 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al from Momordica charantia Acts as PPARγ Ligand

Noruddin NAA, Hamzah MF, Rosman Z, Salin NH, Shu-Chien AC, Muhammad TST

Molecules, 2021 May 03;26(9).
PMID: 34063700 DOI: 10.3390/molecules26092682

Momordica charantia is a popular vegetable associated with effective complementary and alternative diabetes management in some parts of the world. However, the molecular mechanism is less commonly investigated. In this study, we investigated the association between a major cucurbitane triterpenoid isolated from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (THCB) and peroxisome proliferator activated receptor gamma (PPARγ) activation and its related activities using cell culture and molecular biology techniques. In this study, we report on both M. charantia fruit crude extract and THCB in driving the luciferase activity of Peroxisome Proliferator Response Element, associated with PPARγ activation. Other than that, THCB also induced adipocyte differentiation at far less intensity as compared to the full agonist rosiglitazone. In conjunction, THCB treatment on adipocytes also resulted in upregulation of PPAR gamma target genes expression; AP2, adiponectin, LPL and CD34 at a lower magnitude compared to rosiglitazone's induction. THCB also induced glucose uptake into muscle cells and the mechanism is via Glut4 translocation to the cell membrane. In conclusion, THCB acts as one of the many components in M. charantia to induce hypoglycaemic effect by acting as PPARγ ligand and inducing glucose uptake activity in the muscles by means of Glut4 translocation.

Matched MeSH terms: Hepatocytes/cytology
Display of hepatitis B virus PreS1 peptide on bacteriophage T7 and its potential in gene delivery into HepG2 cells

Tang KH, Yusoff K, Tan WS

J Virol Methods, 2009 Aug;159(2):194-9.
PMID: 19490973 DOI: 10.1016/j.jviromet.2009.03.015

Hepatitis B is a major public health problem worldwide which may lead to chronic liver diseases, cirrhosis and hepatocellular carcinoma. An interaction between hepatitis B virus (HBV) envelope protein, particularly the PreS1 region, and a specific cell surface receptor is believed to be the initial step of HBV infection through attachment to hepatocytes. In order to develop a gene delivery system, bacteriophage T7 was modified genetically to display polypeptides of the PreS1 region. A recombinant T7 phage displaying amino acids 60-108 of the PreS1 region (PreS1(60-108)) was demonstrated to be most effective in transfecting HepG2 cells in a dose- and time-dependant manner. The phage genome was recovered from the cell lysate and confirmed by PCR whereas the infectious form of the internalized phage was measured by a plaque-forming assay. The internalized phage exhibited the appearance of green fluorescent dots when examined by immunofluorescence microscopy. Surface modification, particularly by displaying the PreS1(60-108) enhanced phage uptake, resulting in more efficient in vitro gene transfer. The ability of the recombinant phage to transfect HepG2 cells demonstrates the potential of the phage display system as a gene therapy for liver cancer.

Matched MeSH terms: Hepatocytes/virology
Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes

Chew CH, Chew GS, Najimudin N, Tengku-Muhammad TS

Int J Biochem Cell Biol, 2007;39(10):1975-86.
PMID: 17616429

Peroxisome proliferator activated receptor alpha has been implicated as a regulator of acute phase response genes in hepatocytes. Interleukin-6 is widely known as a major cytokine responsible in the regulation of acute phase proteins and, therefore, acute phase response. Unfortunately, to date, very little is understood about the molecular mechanisms by which interleukin-6 regulates the gene expression of peroxisome proliferator activated receptor alpha. Here, we report the molecular mechanisms by which peroxisome proliferator activated receptor alpha was regulated by interleukin-6 in human HepG2 cells. Interleukin-6 was shown to down-regulate the peroxisome proliferator activated receptor alpha gene expression at the level of gene transcription. Functional dissection of human peroxisome proliferator activated receptor alpha promoter B revealed the role of predicted CCAAT/enhancer-binding protein binding site (-164/+34) in mediating the interleukin-6 inhibitory effects on peroxisome proliferator activated receptor alpha mRNA expression and electrophoretic mobility shift assay showed the binding of CCAAT/enhancer-binding protein isoforms to this cis-acting elements was increased in interleukin-6-treated HepG2 cells. Co-transfection experiments, then, demonstrated that CCAAT/enhancer-binding protein beta either in homodimer or heterodimer with CCAAT/enhancer-binding protein alpha and CCAAT/enhancer-binding protein delta plays a predominant role in inhibiting the transcriptional activity of peroxisome proliferator activated receptor alpha promoter B, thus, reducing the peroxisome proliferator activated receptor alpha mRNA expression. These studies, therefore, suggest a novel mechanism for interleukin-6-mediated inhibition of peroxisome proliferator activated receptor alpha gene expression that involves the activation of CCAAT/enhancer-binding protein isoforms with CCAAT/enhancer-binding protein beta may play a major role.

Matched MeSH terms: Hepatocytes/drug effects*; Hepatocytes/metabolism
Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study

Somchit N, Norshahida AR, Hasiah AH, Zuraini A, Sulaiman MR, Noordin MM

Hum Exp Toxicol, 2004 Nov;23(11):519-25.
PMID: 15625777

Itraconazole and fluconazole are oral antifungal drugs, which have a wide spectrum antifungal activity and better efficacy than the older drugs. However, both drugs have been associated with hepatotoxicity in susceptible patients. The mechanism of antifungal drug-induced hepatotoxicity is largely unknown. Therefore, the aim of this present study was to investigate and compare the hepatotoxicity induced by these drugs in vivo. Rats were treated intraperitoneally with itraconazole or fluconazole either single (0, 10, 100 and 200 mg/kg) or subchronic (0, 10, 50 and 100 mg/kg per day for 14 days) doses. Plasma and liver samples were taken at the end of the study. A statistically significant and dose dependent increase of plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities were detected in the subchronic itraconazole-treated group. In addition, dose-dependent hepatocellular necrosis, degeneration of periacinar and mizonal hepatocytes, bile duct hyperplasia and biliary cirrhosis and giant cell granuloma were observed histologically in the same group. Interestingly, fluconazole treated rats had no significant increase in transaminases for both single and subchronic groups. In the subchronic fluconazole treated rats, only mild degenerative changes of centrilobular hepatocytes were observed. These results demonstrated that itraconazole was a more potent hepatotoxicant than fluconazole in vivo in rats.

Matched MeSH terms: Hepatocytes/drug effects; Hepatocytes/pathology
Fulltext Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBV in vitro and in vivo

Leong CR, Funami K, Oshiumi H, Mengao D, Takaki H, Matsumoto M, et al.

Oncotarget, 2016 10 18;7(42):68179-68193.
PMID: 27626689 DOI: 10.18632/oncotarget.11907

Hepatitis B virus (HBV) barely induces host interferon (IFN)-stimulated genes (ISGs), which allows efficient HBV replication in the immortalized mouse hepatocytes as per human hepatocytes. Here we found that transfection of Isg20 plasmid robustly inhibits the HBV replication in HBV-infected hepatocytes irrespective of IRF3 or IFN promoter activation. Transfection of Isg20 is thus effective to eradicate HBV in the infected hepatocytes. Transfection of HBV genome or ε-stem of HBV pgRNA (active pgRNA moiety) failed to induce Isg20 in the hepatocytes, while control polyI:C (a viral dsRNA analogue mimic) activated MAVS pathway leading to production of type I IFN and then ISGsg20 via the IFN-α/β receptor (IFNAR). Consistently, addition of IFN-α induced Isg20 and partially suppressed HBV replication in hepatocytes. Chasing HBV RNA, DNA and proteins by blotting indicated that ISG20 expression decreased HBV RNA and replicative DNA in HBV-transfected cells, which resulted in low HBs antigen production and virus titer. The exonuclease domains of ISG20 mainly participated in HBV-RNA decay. In vivo hydrodynamic injection, ISG20 was crucial for suppressing HBV replication without degrading host RNA in the liver. Taken together, ISG20 acts as an innate anti-HBV effector that selectively degrades HBV RNA and blocks replication of infectious HBV particles. ISG20 would be a critical effector for ameliorating chronic HBV infection in the IFN therapy.

Matched MeSH terms: Hepatocytes/metabolism*; Hepatocytes/virology
Cis-9, Trans-11 Conjugated Linoleic Acid Reduces Phosphoenolpyruvate Carboxykinase Expression and Hepatic Glucose Production in HepG2 Cells

Chai BK, Al-Shagga M, Pan Y, Then SM, Ting KN, Loh HS, et al.

Lipids, 2019 06;54(6-7):369-379.
PMID: 31124166 DOI: 10.1002/lipd.12154

Dysregulated hepatic gluconeogenesis is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM). Although existing drugs have been proven to improve gluconeogenesis, achieving this objective with functional food is of interest, especially using conjugated linoleic acid (CLA) found in dairy products. Both cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12) isomers of CLA were tested in human (HepG2) and rat (H4IIE) hepatocytes for their potential effects on gluconeogenesis. The hepatocytes exposed for 24 h with 20 μM of c9,t11-CLA had attenuated the gluconeogenesis in both HepG2 and H4IIE by 62.5% and 80.1%, respectively. In contrast, t10,c12-CLA had no effect. Of note, in HepG2 cells, the exposure of c9,t11-CLA decreased the transcription of gluconeogenic enzymes, cytosolic phosphoenolpyruvate carboxykinase (PCK1) by 87.7%, and glucose-6-phosphatase catalytic subunit (G6PC) by 38.0%, while t10,c12-CLA increased the expression of G6PC, suggesting the isomer-specific effects of CLA on hepatic glucose production. In HepG2, the peroxisome proliferator-activated receptor (PPAR) agonist, rosiglitazone, reduced the glucose production by 72.9%. However, co-administration of c9,t11-CLA and rosiglitazone neither exacerbated nor attenuated the efficacy of rosiglitazone to inhibit glucose production; meanwhile, t10,c12-CLA abrogated the efficacy of rosiglitazone. Paradoxically, PPARγ antagonist GW 9662 also led to 70.2% reduction of glucose production and near undetectable PCK1 expression by abrogating CLA actions. Together, while the precise mechanisms by which CLA isomers modulate hepatic gluconeogenesis directly or via PPAR warrant further investigation, our findings establish that c9,t11-CLA suppresses gluconeogenesis by decreasing PEPCK on hepatocytes.

Matched MeSH terms: Hepatocytes/metabolism*; Hepatocytes/chemistry
Antioxidant, α-amylase and α-glucosidase activity of various solvent fractions of I. obliquus and the preventive role of active fraction against H2 O2 induced damage in hepatic L02 cells as fungisome

Gao X, Santhanam RK, Xue Z, Jia Y, Wang Y, Lu Y, et al.

J Food Sci, 2020 Apr;85(4):1060-1069.
PMID: 32147838 DOI: 10.1111/1750-3841.15084

Inonotus obliquus is a traditional mushroom well known for its therapeutic value. In this study, various solvent fractions of I. obliquus were preliminarily screened for their antioxidant, α-amylase and α-glucosidase inhibition properties. To improve the drug delivery, the active fraction (ethyl acetate fraction) of I. obliquus was synthesized into fungisome (ethyl acetate phophotidyl choline complex, EAPC) and its physical parameters were assessed using Fourier transform infrared spectroscopy (FTIR), High performance liquid chromatography (HPLC), Scanning electron microscope (SEM), and ς potential analysis. Then normal human hepatic L02 cells was used to evaluate the cytotoxicity of EAPC. The results showed that EA fraction possesses significant free radical scavenging, α-amylase and α-glucosidase inhibition properties. FTIR, SEM, and HPLC analysis confirmed the fungisome formation. The particle size of EAPC was 102.80 ± 0.42 nm and the ς potential was -54.30 ± 0.61 mV. The percentage of drug entrapment efficiency was 97.13% and the drug release rates of EAPC in simulated gastric fluid and simulated intestinal fluid were 75.04 ± 0.29% and 93.03 ± 0.36%, respectively. EAPC was nontoxic to L02 cells, however it could selectively fight against the H2 O2 induced oxidative damage in L02 cells. This is the first study to provide scientific information to utilize the active fraction of I. obliquus as fungisome. PRACTICAL APPLICATIONS: Inonotus obliquus (IO) is a traditional medicinal fungus. The extracts of IO have obvious antioxidant and hypoglycemic activities. Ethyl acetate (EA) fraction of IO was encapsulated in liposomes to form EAPC. EAPC has a sustained-release effect. It has nontoxic to L02 cells and could protect L02 cells from oxidative damage caused by hydrogen peroxide. This study could provide new ideas for the treatment of diabetes.

Matched MeSH terms: Hepatocytes/drug effects; Hepatocytes/metabolism
Investigation of highly unsaturated fatty acid metabolism in the Asian sea bass, Lates calcarifer

Mohd-Yusof NY, Monroig O, Mohd-Adnan A, Wan KL, Tocher DR

Fish Physiol Biochem, 2010 Dec;36(4):827-43.
PMID: 20532815 DOI: 10.1007/s10695-010-9409-4

Lates calcarifer, commonly known as the Asian sea bass or barramundi, is an interesting species that has great aquaculture potential in Asia including Malaysia and also Australia. We have investigated essential fatty acid metabolism in this species, focusing on the endogenous highly unsaturated fatty acid (HUFA) synthesis pathway using both biochemical and molecular biological approaches. Fatty acyl desaturase (Fad) and elongase (Elovl) cDNAs were cloned and functional characterization identified them as ∆6 Fad and Elovl5 elongase enzymes, respectively. The ∆6 Fad was equally active toward 18:3n-3 and 18:2n-6, and Elovl5 exhibited elongation activity for C18-20 and C20-22 elongation and a trace of C22-24 activity. The tissue profile of gene expression for ∆6 fad and elovl5 genes, showed brain to have the highest expression of both genes compared to all other tissues. The results of tissue fatty acid analysis showed that the brain contained more docosahexaenoic acid (DHA, 22:6n-3) than flesh, liver and intestine. The HUFA synthesis activity in isolated hepatocytes and enterocytes using [1-(14)C]18:3n-3 as substrate was very low with the only desaturated product detected being 18:4n-3. These findings indicate that L. calcarifer display an essential fatty acid pattern similar to other marine fish in that they appear unable to synthesize HUFA from C18 substrates. High expression of ∆6 fad and elovl5 genes in brain may indicate a role for these enzymes in maintaining high DHA levels in neural tissues through conversion of 20:5n-3.

Matched MeSH terms: Hepatocytes/metabolism
Design, synthesis, in vitro evaluation, molecular docking and ADME properties studies of hybrid bis-coumarin with thiadiazole as a new inhibitor of Urease

Alomari M, Taha M, Imran S, Jamil W, Selvaraj M, Uddin N, et al.

Bioorg Chem, 2019 11;92:103235.
PMID: 31494327 DOI: 10.1016/j.bioorg.2019.103235

Hybrid bis-coumarin derivatives 1-18 were synthesized and evaluated for their in vitro urease inhibitory potential. All compounds showed outstanding urease inhibitory potential with IC50 value (The half maximal inhibitory concentration) ranging in between 0.12 SD 0.01 and 38.04 SD 0.63 µM (SD standard deviation). When compared with the standard thiourea (IC50 = 21.40 ± 0.21 µM). Among these derivatives, compounds 7 (IC50 = 0.29 ± 0.01), 9 (IC50 = 2.4 ± 0.05), 10 (IC50 = 2.25 ± 0.05) and 16 (IC50 = 0.12 ± 0.01) are better inhibitors of the urease compared with thiourea (IC50 = 21.40 ± 0.21 µM). To find structure-activity relationship molecular docking as well as absorption, distribution, metabolism, and excretion (ADME) studies were also performed. Various spectroscopic techniques like 1H NMR, 13C NMR, and EI-MS were used for characterization of all synthesized analogs. All compounds were tested for cytotoxicity and found non-toxic.

Matched MeSH terms: Hepatocytes/drug effects
A preliminary study of the effects of an extract of Ligularia fischeri leaves on type II collagen-induced arthritis in DBA/1J mice

Choi EM, Kim YH

Food Chem Toxicol, 2008 Jan;46(1):375-9.
PMID: 17904263 DOI: 10.1016/j.fct.2007.08.018

The present study was undertaken to determine whether Ligularia fischeri leaf extract (LF) is efficacious against collagen-induced arthritis (CIA) in mice. DBA/1J mice were immunized with bovine type II collagen and treated with LF (100 and 200 mg/kg) for 49 days. Mice were assessed regularly for signs of arthritis and the levels of rheumatoid factor, anti-type II collagen antibody, cytokines, AST, ALT, and creatinine in serum were also examined after the animals were killed. The arthritis score and paw edema were markedly suppressed in the groups treated with LF. Moreover, levels of rheumatoid factor, anti-type II collagen antibody, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 in sera were reduced by LF administration. These data suggest that L. fischeri might be effective for the treatment of inflammatory arthritis like human rheumatoid arthritis.

Matched MeSH terms: Hepatocytes/drug effects
Toxicological evaluation of some Malaysian locally processed raw food products

Sharif R, Ghazali AR, Rajab NF, Haron H, Osman F

Food Chem Toxicol, 2008 Jan;46(1):368-74.
PMID: 17900779

Malaysian locally processed raw food products are widely used as main ingredients in local cooking. Previous studies showed that these food products have a positive correlation with the incidence of cancer. The cytotoxicity effect was evaluated using MTT assay (3-(4,5-dimetil-2-thiazolil)-2,5-diphenyl-2H-tetrazolium bromide) against Chang liver cells at 2000 microg/ml following 72 h incubation. Findings showed all methanol extracts caused a tremendous drop in the percentage of cell viability at 2000 microg/ml (shrimp paste - 41.69+/-3.36%, salted fish - 37.2+/-1.06%, dried shrimp - 40.32+/-1.8%, p<0.05). To detect DNA damage in a single cell, alkaline Comet Assay was used. None of the extracts caused DNA damage to the Chang liver cells at 62.5 microg/ml following 24 h incubation, as compared to the positive control, hydrogen peroxide (tail moment - 9.50+/-1.50; tail intensity - 30.50+/-2.50). Proximate analysis which was used for the evaluation of macronutrients in food showed that shrimp paste did not comply with the protein requirement (<25%) as in Food Act 1983. Salt was found in every sample with the highest percentage being detected in shrimp paste which exceeded 20%. Following heavy metal analysis (arsenic, cadmium, lead and mercury), arsenic was found in every sample with dried shrimps showing the highest value as compared to the other samples (6.16 mg/kg). In conclusion, several food extracts showed cytotoxic effect but did not cause DNA damage against Chang liver cells. Salt was found as the main additive and arsenic was present in every sample, which could be the probable cause of the toxicity effects observed.

Matched MeSH terms: Hepatocytes/drug effects
EGCG exerts its protective effect by mitigating the release of lysosomal enzymes in aged rat liver on exposure to high cholesterol diet

Ravindran R, Jaganathan R, Periandavan K

Cell Biochem Funct, 2020 Apr;38(3):309-318.
PMID: 31926118 DOI: 10.1002/cbf.3490

The aim is to test the hypothesis whether the cholesterol loaded lysosomes are capable of mediating lysosomal membrane permeabilization (LMP) during aging and to study the efficacy of epigallocatechin-3-gallate (EGCG) in preserving the lysosomal membrane stability. Aged rats were fed with high cholesterol diet (HCD) and treated with EGCG orally. Serum and tissue lipid status, cholesterol levels in lysosomal fraction, activities of lysosomal enzymes in lysosomal, and cytosolic fractions were measured. Transmission electron microscopic studies (TEM), oil red "O" (ORO) staining, and immunohistochemical analysis of oxidized low density lipoprotein (OxLDL) were carried out. Significant increase in serum, tissue lipid profile, and lysosomal cholesterol levels were observed in aged HCD-fed rats with a concomitant decrease in high density lipoprotein (HDL) levels. We also observed a significant increase in lipid accumulation in hepatocytes of aged HCD-fed rats by TEM, ORO, and immunohistochemical staining. Upon treatment with EGCG to aged HCD-fed animals, we found augmented levels of HDL with a concomitant decrease in lysosomal cholesterol levels and other lipoproteins. TEM studies and immunohistochemistry of OxLDL also showed a marked reduction in lipid deposition of hepatocytes. Thus, EGCG has preserved the lysosomal membrane stability in HCD stressed aged rats. SIGNIFICANCE OF THE STUDY: The research article is focused mainly on the effect of EGCG and its capability on mitigating the release of lysosomal enzymes in aged animals fed with HCD. The study signifies the cellular function of the organelle lysosome following administration of aged rats with HCD, which would make the readers to understand the action of EGCG and the interrelationship of both cholesterol and activity of lysosomes when cholesterol is loaded.

Matched MeSH terms: Hepatocytes/drug effects
Cutaneous metastasis of hepatocellular carcinoma diagnosed by fine needle aspiration cytology and Hep Par 1 immunopositivity

Isa NM, Bong JJ, Ghani FA, Rose IM, Husain S, Azrif M

Diagn Cytopathol, 2012 Nov;40(11):1010-4.
PMID: 21563319 DOI: 10.1002/dc.21706

Cutaneous metastasis of hepatocellular carcinoma (HCC) is very rare, accounting for less than 0.8% of all known cutaneous metastases and occurring in 2.7-3.4% of HCCs. With less than 50 such cases reported worldwide, most of which were diagnosed histologically on excised lesions, it can only be expected that diagnosis made on cytological features alone would be challenging. We report a case of cutaneous metastasis of HCC diagnosed based on cytological features and confirmed by Hep Par 1 immunopositivity of the cell block material. An 81-year-old man, who was known to have unresectable HCC, presented with a 1-month history of painless, left nasal alae mass. The mass measured 1.5 cm in diameter, and was multilobulated with a central necrosis. Fine needle aspiration of the mass was done. Smears were cellular, comprising of malignant cells in loose clusters and aggregates as well as singly dispersed. The malignant cells displayed moderate nuclear pleomorphism, occasional prominent nucleoli, and intranuclear pseudoinclusion. Cell block material demonstrated the trabeculae pattern of the malignant cells and Hep Par 1 immunopositivity. The final diagnosis of a metastatic cutaneous HCC was made. In conclusion, cutaneous HCC metastasis is rare and should be considered in the differential diagnosis in patients with a history of HCC presenting with suspicious skin lesion. In the right clinical setting, a confident diagnosis can be made in such cases by using the fine needle aspiration technique aided with immunopositivity for Hep Par 1 antibody of the aspirated material.

Matched MeSH terms: Hepatocytes/pathology
Fulltext Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in non-alcoholic fatty liver disease

Lai LL, Chan WK, Sthaneshwar P, Nik Mustapha NR, Goh KL, Mahadeva S

PLoS One, 2017;12(4):e0174982.
PMID: 28369100 DOI: 10.1371/journal.pone.0174982

Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) has been suggested to be useful for the assessment of disease severity in non-alcoholic fatty liver disease (NAFLD). Consecutive adult NAFLD patients who had a liver biopsy were included. Serum WFA+-M2BP level was measured using a lectin-antibody sandwich immunoassay using a chemiluminescence enzyme immunoassay machine (HISCL-5000, Sysmex, Kobe, Japan). The measured levels were indexed using the following equation: Cut-off index (COI) = ([WFA+-M2BP]sample-[WFA+-M2BP]NC) / ([WFA+-M2BP]PC-[WFA+-M2BP]NC), where PC = positive control and NC = negative control. Histopathological examination of liver biopsy specimen was reported according to Non-Alcoholic Steatohepatitis (NASH) Clinical Research Network Scoring System. Data for 220 cases were analyzed. The AUROC of the COI for the diagnosis of NASH was 0.65. The AUROC of the COI for the diagnosis of steatosis grade ≥2 and 3 was 0.64 and 0.53, respectively. The AUROC of the COI for the diagnosis of lobular inflammation grade ≥1, ≥2 and 3 was 0.57, 0.68 and 0.59, respectively. The AUROC of the COI for the diagnosis of hepatocyte ballooning grade ≥1 and 2 was 0.64 and 0.65, respectively. The AUROC of the COI for the diagnosis of fibrosis stage ≥1, ≥2, ≥3 and 4 was 0.61, 0.71, 0.74 and 0.84, respectively. Out of the 220 cases, 152 cases were the same 76 patients who had a repeat liver biopsy after 48 weeks of intervention. The AUROC of the change in the COI to detect improvement in steatosis, lobular inflammation, hepatocyte ballooning and fibrosis was 0.57, 0.54, 0.59 and 0.52, respectively. In conclusion, serum WFA+-M2BP was most useful for the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis in NAFLD patients. However, it was less useful for differentiating NASH from non-NASH, and for diagnosis and follow-up of the individual histopathological components of NASH.

Matched MeSH terms: Hepatocytes/pathology
Physicochemical Characterization of Mitragyna speciosa Alkaloid Extract and Mitragynine using In Vitro High Throughput Assays

Kong WM, Chik Z, Mohamed Z, Alshawsh MA

Comb Chem High Throughput Screen, 2017;20(9):796-803.
PMID: 29076424 DOI: 10.2174/1386207320666171026121820

AIM AND OBJECTIVE: Mitragynine, a major active alkaloid of Mitragyna speciosa, acts as an agonist on µ-opioid receptors, producing effects similar to morphine and other opioids. It has been traditionally utilized to alleviate opiate withdrawal symptoms. Besides consideration about potency and selectivity, a good drug must possess a suitable pharmacokinetic profile, with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile, in order to have a high chance of success in clinical trials.
MATERIAL AND METHOD: The purity of mitragynine in a Mitragyna speciosa alkaloid extract (MSAE) was determined using Ultra-Fast Liquid Chromatography (UFLC). In vitro high throughput ADMETox studies such as aqueous solubility, plasma protein binding, metabolic stability, permeability and cytotoxicity tests were carried out to analyze the physicochemical properties of MSAE and mitragynine. The UFLC quantification revealed that the purity of mitragynine in the MSAE was 40.9%.
RESULTS: MSAE and mitragynine are highly soluble in aqueous solution at pH 4.0 but less soluble at pH 7.4. A parallel artificial membrane permeability assay demonstrated that it is extensively absorbed through the semi-permeable membrane at pH 7.4 but very poorly at pH 4.0. Both are relatively highly bound to plasma proteins (> 85 % bound) and are metabolically stable to liver microsomes (> 84 % remained unchanged). In comparison to MSAE, mitragynine showed higher cytotoxicity against WRL 68, HepG2 and Clone 9 hepatocytes after 72 h treatment.
CONCLUSION: The obtained ADME and cytotoxicity data demonstrated that both MSAE and mitragynine have poor bioavailability and have the potential to be significantly cytotoxic.

Matched MeSH terms: Hepatocytes/drug effects
HPLC profiling of phenolics and flavonoids of Adonidia merrillii fruits and their antioxidant and cytotoxic properties

Vafaei A, Bin Mohamad J, Karimi E

Nat Prod Res, 2019 Sep;33(17):2531-2535.
PMID: 29527930 DOI: 10.1080/14786419.2018.1448810

In this study the antioxidant and cytotoxicity activity of the Adonidia merrillii fruits were investigated using different solvent polarities (methanol, ethyl acetate and water). The results showed that the total phenolic and flavonoid contents of the methanolic extract was higher compare with other extract with respective values of 17.80 ± 0.45 mg gallic acid equivalents/g dry weight (DW) and 5.43 ± 0.33 mg rutin equivalents/g DW. Beside that The RP-HPLC analyses indicated the presence of gallic acid, pyrogallol, caffeic acid, vanillic acid, syringic acid, naringin and rutin. In the DPPH, NO2 and ABTS scavenging assays, the methanolic extract exhibited higher antioxidant activity as compared to the ethyl acetate and water extracts. The extracts exhibited moderate to weak cytotoxic activity in the assays using human hepatocytes (Chang liver cells) and NIH/3T3 (fibroblasts cell) cell lines. The findings showed the Adonidia merrillii fruit extracts to possess considerable antioxidant and cytotoxicity properties. The fruit, therefore, is a potential candidate for further work to discover antioxidant and cytotoxic drugs from natural sources.

Matched MeSH terms: Hepatocytes/drug effects

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