Induction Of Hepatocellular Carcinoma Research Articles

MicroRNA-195 vector influence on the development of gradually induced hepatocellular carcinoma in murine model

ABSTRACTBackground: Recent studies implicate the role of microRNAs in the pathogenesis of hepatocellular carcinoma (HCC). This study was designed to induce HCC, in an experimental model, with the prospect to study the molecular pathophysiologic changes accompanying the development of HCC and the effect of miRNA-195 vector on the process of hepatocarcinogenesis.Methodology: This study incorporated three groups of male albino mice; one control group and two other groups injected intraperitoneal with diethylnitrosamine (DEN) weekly for 12 weeks for the gradual induction of HCC. The third group was injected intra-hepatic with miR-195 vector 1 month after DEN injection. At the 8th and 12th weeks post-DEN treatment, the tumor-associated biomarkers alpha-fetoprotein (AFP), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-α) were assessed in the serum of all mice. Hepatic specimens were subjected to ultra-structural pathological examination as well as to caspase-3 and survivin genes expression analysis.Results: All the assessed serological and molecular parameters of HCC development, in the miRNA-195-treated group of mice, showed a significant increase, versus the DEN-treated group, whereas survivin was significantly down-regulated, in the miR-195-treated group (P < 0.001). Additionally, ultra-structural criteria of HCC were depicted, in the 12th week, in DEN-injected group, versus the 8th week, in the miRNA-195-treated group.Conclusions: Intra-hepatic injection of miRNA-195 vector induced apoptotic gene expression and suppressed anti-apoptotic gene but these favorable anti-cancer effects could not counteract the inflammatory, and subsequently, the oncogenic effect probably caused by vector administration. Therefore, further studies are required to investigate the effect of miRNA in combination with anti-inflammatory medications.

Effect of cetyltrimethylammonium bromide surfactant coated Curcumin copper nanocomposite on hepatocellular carcinoma in rats

This study was designed to investigate the role of (Curcumin/ Copper / cetyltrimethylammonium bromide) nano particles complex against hepatocellular carcinoma (HCC) induced in rats. Forty rats were divided into four groups. Group 1(negative control group): normal rats. Group 2 (Diethylnitrosamine) (DEN): rats administrated orally DEN with a dose of 20 mg/kg b. wt., five times a week / 6 weeks for HCC induction. Group 3 (protective ): rats were orally treated with Curcumin/ CU / CTAB (dissolved in Tween-80 (1 %) in 0.9 % normal saline) at a dose of 35 mg/kg b. wt., five times a week / 15 weeks as 2 weeks before DEN then, during administration of DEN and 15 weeks after DEN administration. Group 4 )treated group) rats treated with Curcumin/ CU/ CTAB dissolved in Tween-80 (1 %) in 0.9 % normal saline), at a dose of 35 mg/kg b. wt., five times a week / 15 weeks, following the administration of DEN for 6 weeks . Injection of DEN induced a significant increase in serum level of alpha-fetoprotein (AFP), alpha-L-fucosidase activity (AFU) and vascular endothelial growth factor (VEGF). On other hand, marked depletion in tissue antioxidants including superoxide dismutase (SOD), glutathione perioxidase (GPX) activities, and reduced glutathione (GSH) concentration. Administration of (Curcumin/ CU/ CTAB) nano composite was able to prevent cellular damage induced by reactive oxygen species (ROS) and able to make changes of tumor markers and tissue antioxidants nearly toward control.

Selective toxicity of chrysin on mitochondria isolated from liver of a HCC rat model

Flavonoids are natural compounds that show various biological effects, such as the anti-cancer effect. Chrysin is a flavonoid compound found in honey and propolis. Studies have shown that chrysin has anti-cancer activity due to induction of apoptosis signaling. In the present study, we examined the cytotoxic effect of chrysin against liver mitochondria obtained from the hepatocellular carcinoma (HCC) rat model. Diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) was used for induction of HCC. Mitochondria were isolated from liver hepatocytes using differential centrifugation. Then, hepatocytes and mitochondria markers related to apoptosis signaling were investigated. Our finding indicated an increase in mitochondrial reactive oxygen species (ROS) generation, collapse in the mitochondrial membrane potential (MMP), swelling in mitochondria, and cytochrome c release (about 1.6 fold) after exposure of mitochondria obtained from the HCC rats group with chrysin (10, 20, and 40 µM) compared to the normal rats group. Furthermore, Chrysin was able to increase caspase-3 activity in the HCC rats group (about 2.4 fold) compared to the normal rats group. According to the results, we proposed that chrysin could be considered as a promising complementary therapeutic candidate for the treatment of HCC, but it requires a further in vivo and clinical studies.

Elevated Expression of Cytosolic Phospholipase A2 Delta Is Associated with Lipid Metabolism Dysregulation during Hepatocellular Carcinoma Progression.

Objective Liver cancer is the third rank amongst the common malignancies, causing maximum death in the patients diagnosed with cancers. Currently available biomarkers are not enough sensitive for early diagnosis of hepatocellular carcinoma (HCC). This makes difficult management of HCC. With the aim of finding new generation of proteomic-based biomarkers, the represented study was designed to characterize the differentially expressed proteins at different stages of HCC initiation and at progression. This could lead to find potential biomarkers for early detection of HCC. Materials and Methods In this experimental study, we report induction of HCC by administrating chemical carcinogens in male Wistar rats. Disease progression was monitored by histological evaluation. Serum proteomic analyses such as 2 dimensional (2D)-electrophoresis, MALDI-TOF-MS/MS and Western blot have been used to analyze and characterize the differentially expressed proteins during HCC development. Results HCC initiation and tumorigenesis were observed at one and four months post carcinogen treatment, respectively. One of the differentially-expressed proteins, namely, cytosolic phospholipase A2delta was significantly up-regulated at very early stage of HCC development. Its expression continued to increase during cancer progression and hepatotumorigenesis stages. Its elevated expression has been confirmed by Western blot analysis. Consistent to this, analyses of the sera in the clinically confirmed liver cancer patients showed elevated expression of this protein, further validating our experimental results. ConclusionThis study suggests that elevation in the expression of cytosolic phospholipase A2delta is associated with progression of HCC.

Promyelocytic leukemia protein deficiency leads to spontaneous formation of liver tumors in hepatitis C virus transgenic mice.

Persistent infection with hepatitis C virus (HCV) is a known risk factor for the development of hepatocellular carcinoma (HCC). The lack of the tumor suppressor promyelocytic leukemia protein (PML) in combination with HCV fosters hepatocarcinogenesis via induction of HCC using diethylnitrosamine (DEN) in a rodent model. However, the spontaneous development of malignant lesions in PML‐deficient mice with an HCV‐transgene (HCVtg) has not been investigated thus far. We crossed PML‐deficient mice with HCV transgene expressing mice and observed the animals for a period of 12 months. Livers were examined macroscopically and histologically. Gene expression analysis was performed on these samples, and compared with expression of selected genes in human samples of patients undergoing liver transplantation for HCC. In vitro studies were performed in order to analyze the selected pathways. Genetic depletion of PML in combination with HCVtg coincided with an increased hepatocyte proliferation, resulting in development of HCCs in 40% of the PML‐deficient livers. No tumor development was observed in mice with either the PML‐knockout (PML−/−) or HCVtg alone. Gene expression profiling uncovered pathways involved in cell proliferation, such as NLRP12 and RASFF6. These findings were verified in samples from human livers of patients undergoing liver transplantation for HCC. Further in vitro studies confirmed that lack of PML, NLRP12, and RASFF6 leads to increased cell proliferation. The lack of PML in combination with HCV is associated with increased cell proliferation, fostering tumor development in the liver. Our data demonstrate that PML acts as an important tumor suppressor in HCV‐dependent liver pathology.

Effect of protocatechuic acid-layered double hydroxide nanoparticles on diethylnitrosamine/phenobarbital-induced hepatocellular carcinoma in mice.

Researchers investigating cancer chemotherapy and management continue to search for agents that selectively kill malignant cells and leave healthy neighboring cells intact. Natural products provide relevant resources for anti-cancer drug discovery. However, the physicochemical properties of these compounds limit their efficient uptake and bioavailability. We introduced a nanocarrier system, namely, zinc-aluminum-layered double hydroxide (ZnAl-LDH) intercalated with protocatechuic acid. In this study, the efficacy and toxicity of protocatechuic acid intercalated in zinc aluminum-layered double hydroxide nanoparticles (PCA-ZnAl) against diethylnitrosamine/phenobarbital (DEN/PB)-induced hepatocellular carcinoma (HCC) in BALB/c mice was evaluated. HCC in male mice was induced by a single-dose intraperitoneal administration of DEN and was promoted by the introduction of PB via drinking water for 12 weeks. HCC induction was confirmed after the DEN/PB introduction period by measurement of the elevated level of serum α-feto protein (AFP). The results showed that the level of α-fetoprotein was significantly reduced in PCA-ZnAl (350±43.90 ng/mL), doxorubicin (DOX) (290±20.52 ng/mL) and ZnAl-LDH (390±19.65 ng/mL) treated animals compared to HCC mice treated with normal saline (580.4± 52.04 ng/mL). Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were significantly increased, whereas the level of lipid peroxidation was significantly decreased in HCC mice treated with DOX, PCA-ZnAl and ZnAl-LDH compared with those in HCC mice treated with saline. Restoration of hepatocyte morphology was observed following treatment that was comparable to that in the normal control group. Deterioration of hepatic cells and a significant increase of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were observed in the cancer-induced untreated group compared with that in the groups treated with nanoparticles. The histopathological features of the liver obtained from PCA-ZnAl-treated mice showed a uniform size with a similar distribution of the nuclear-cytoplasmic ratio and nucleus centrally located in the cytoplasm, similar to the normal liver cells. The results underscored the potential of PCA-ZnAl for the treatment of hepatocellular carcinoma.

Characterization of rare NEIL1 variants found in East Asian populations

The combination of chronic dietary exposure to the fungal toxin, aflatoxin B1 (AFB1), and hepatitis B viral (HBV) infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB1 exposed. AFB1-induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB1-induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeoxynucleotide containing a site-specific AFB1-formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.

Chemopreventive Efficacy of &lt;i&gt;Punica granatum&lt;/i&gt; and &lt;i&gt;Silybum marianum &lt;/i&gt;Extracts on Chemically-induced Hepatocellular Carcinoma in Rats

Punica granatum (POM) and Silybum marianum (MT) receiving attention as potential potent anti-oxidant and anti-mutant agents. In this context, the present study was designed to highlight their effects either in vitro as well as in vivo model of induced Hepatocellular carcinoma (HCC). Human hepatoma (HepG2 cells) were treated with MT and POM to explore their antitumor activity then in vivo were carried out on thirty-six male albino rats divided into six groups (n=6). Two weeks after induction of HCC, rats were co-treated with either MT or POM ethanolic extract (500 mg/kg, orally) daily for 8 weeks. The results displayed marked reduction in the viability of HepG2 cells with IC50 equal to 48.4 and 8.6 μg/mL of POM and MT treatment respectively. Considering, in vivo experiment HCC group displayed significant elevation liver function indices (p&lt;0.05). It also elicited depletion of liver reduced glutathione (GSH), and increased content of liver malondialdehyde (MDA) compared to control group. HCC was proved after a significantly elevated alpha-fetoprotein (AFP) level (p&lt;0.05). All of these measurements were diminished significantly after POM and MT treatments, except the GSH level that was increased significantly. Supplementation of pomegranate and milk thistle extracts had a protective effect against chemically induced HCC.Â

HCC Specific Protein Network Involving Interactions of EGFR with A-Raf and Transthyretin: Experimental Analysis and Computational Biology Correlates.

The network interactions link human disease proteins to regulatory cellular pathways leading to better understanding of protein functions and cellular processes. Revealing the network of signaling pathways in cancer through protein-protein interactions at molecular level enhances our understanding of Hepatocellular Carcinoma (HCC). A rodent model for study of HCC was developed to identify differentially expressed proteins at very early stage of cancer initiation and throughout its progression. HCC was induced by administrating N-Nitrosodiethylamine (DEN) and 2-aminoacetylfluorine (2-AAF) to male Wistar rats. Proteomic approaches such as 2D-Electrophoresis, PD-Quest, MALDI-TOF-MS and Western blot analyses have been used to identify, characterize and validate the differentially expressed proteins in HCC-bearing animals vis-a-vis controls. The step-wise analysis of morphological and histological parameters revealed HCC induction and tumorigenesis at 1 and 4 months after carcinogen treatment, respectively. We report a novel protein network of 735 different proteins out of which eight proteins are characterized by MALDI-TOF-MS analysis soon after HCC was chemically induced in rats. We have analyzed four different novel routes representing the association of experimentally identified proteins with HCC progression. The study suggests that A-Raf, transthyretin and epidermal growth factor receptor play major role in HCC progression by regulating MAPK signaling pathway and lipid metabolism leading to continuous proliferation, neoplastic transformation and tumorigenesis.

Serum histamine and acetylcholine variations as new noninvasive biochemical markers in staging of experimental hepatocellular carcinoma.

Angiogenesis is a major prerequisite for hepatocellular carcinoma (HCC) development and progression. The present study aims to assess the potential role of two endogenous regulators of angiogenesis histamine (His) and acetylcholine (Ach), as possible biochemical markers for staging of HCC. Five groups of rats were used in this study: a control healthy group (I), another 4 intoxicated groups used for the induction of HCC with a high dose of diethyl nitrosamine (DENA, 200mg/kg, single I.P. dose), (II, III, IV, and V). Groups II, III, IV, and V were killed following 8, 16, 24, and 32weeks after DENA injection, respectively. Serum level of His and Ach was estimated using high-performance liquid chromatography technique coupled with diode array detector (HPLC-DAD), and alpha-fetoprotein (AFP) was measured using ELISA technique along with liver histological examination for all groups. Progression of HCC was estimated by histopathological examination. The results exhibited prominent increase in serum His and Ach levels during the early stages of HCC in group II, III in comparison with the control, and then His serum level declined to the normal level during the last stage of HCC development (group V).However, Ach elevation continued. AFP serum level showed marked increase, till 32 weeks after hepatocarcinogenesis. The decreased histamine level, combined to elevated AFP, indicates an early stage, while continued elevation of Ach with decreased His levels indicates a later stage of HCC. The combination of these two neurotransmitters to AFP may contribute to a noninvasive biochemical staging for HCC.

Protective role of fucoxanthin in diethylnitrosamine-induced hepatocarcinogenesis in experimental adult rats.

Hepatocellular carcinoma (HCC) accounts for majority of cancer related deaths. Two major risk factors in induction of HCC are chemical and virus, however, the possible mechanisms of their differences remain indefinable. The current study focused on protective role of Fucoxanthin (Fx) in liver affected by diethylnitrosamine (DEN)-induced HCC. In this study, levels of liver enzymes, oxidative stressors, antioxidant status, and lipoproteins were compared both in tissue and blood. Tissues were also analyzed extensively by histological studies using H and E staining and transmission electron microscopy (TEM). Rats were clustered into four groups of six experimental animals. Group I: Control rats were administered isotonic saline intraperitoneal Group II: Animals received 0.01% DEN through drinking water to induce hepatocellular carcinoma. Group III: Animals received 0.01% DEN simultaneously oral supplementation of Fx (50 mg/kg b.w). Group IV: Rats were given Fx alone (50 mg/kg b.w) orally and the treatment is for 15 weeks. Results showed the decrease in body weight, serum albumin, antioxidant enzymes, and increased all the liver enzymes, serum bilirubin, and stress markers in DEN induced rats, where as the simultaneous supplementation of Fx reverted them to normal levels. Administration of only Fx did not show any change. Therefore, Fx may serve as a chemotherapeutic agent against liver cancer.

Immunotherapeutic strategies for treatment of hepatocellular carcinoma with antigen-loaded dendritic cells: in vivo study.

Hepatocellular carcinoma (HCC) is one of the major health problems in the world. DCs-based vaccines are a promising immunotherapeutic strategy that aims at the optimal for induction of a specific antitumor immune response and destruction of tumor cells. The present study was conducted to investigate the immunogenic characters of whole tumor lysate-pulsed DCs vaccine and its ability to induce a specific antitumor immune response in HCC mice model. We also evaluate the effectiveness of prophylactic and therapeutic immunization strategies against HCC in mice models. Mice-derived DCs were in vitro loaded with whole tumor lysate prepared from liver tissue of HCC mice and evaluated for expression of surface maturation markers CD83 and CD86. In vivo immunization of mice with whole tumor lysate-pulsed DCs was performed in two strategies; prophylactic (pre-exposure to HCC) and therapeutic (post-exposure to HCC). Effectiveness of both protocols was investigated in terms of histopathological examination of liver sections and measurement of serum levels of immune cytokines interferon-γ (IFN-γ) and interleukin-2 (IL-2). Loading of DCs with whole tumor cell lysate exhibited a significant increase in expression of CD83 and CD86. In vivo administration of prophylactic doses of whole tumor lysate-pulsed DCs in mice before induction of HCC evokes a strong antitumor immune response presented by absence of malignant cells in liver sections and the significant increase in IFN-γ and IL-2. Data herein indicated that prophylactic vaccination with whole tumor lysate-pulsed DCs exhibited an effective antitumor immune response against HCC more than therapeutic protocol.

Evaluation of the anticancer activity of a newly synthetic combretastatine analogue against hepatocellular carcinoma.

Combretastatin A‐4 has been emerged as a promising vascular disrupting agent, which displayed potent cytotoxic activities against a wide range of human cancer cell lines. Therefore, the present study was conducted to evaluate the anticancer activity of a newly synthesized combretastatin A‐4 analogue (1‐(3,4‐Dimethoxyphenyl)‐N‐(2‐methoxyphenyl)‐5‐(3,4,5‐trimethoxyphenyl)‐1H‐1,2,4‐triazole‐3‐carboxamide) against hepatocellular carcinoma (HCC) both in vitro and in vivo. In vitro study used HepG2 cell lines to evaluate the cytotoxic (antitumour) activity, tubulin protein inhibition and cell cycle analysis. While, in vivo study used DENA + CCl4 as a well‐established model for HCC induction in rats. Animal groups were divided as following: Normal non‐treated group, DENA + CCl4 group, CA4‐P treated group and CA4‐P analogue treated group. The following parameters were determined: hepatic relative weight, number of hepatic nodules, relative volume of hepatic nodules, hepatic tissue content of tubulin, histopathological examination of the hepatic tissue, hepatic tissue lipid peroxidation, hepatic tissue carbonyl content, serum ALT, serum AST, hepatic tissue TNF‐α and hepatic AFP concentrations. CA4‐P analogue significantly decreased liver relative weight, number of hepatic nodules and there relative volumes, tubulin content of the hepatic tissue, GSH and AFP which were more pronounced than CA4‐P group. Whereas a marked increase in MDA, carbonyl content and TNF‐a inside hepatic tissue were observed in the CA4‐P analogue treated group, which were higher than CA4‐P group. In conclusion CA4‐P analogue has a potential anti‐cancer activity against hepatocellular carcinoma and this effect was more noticeable than its parent drug (CA4‐P).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chemosensitizing effect of Alpinia officinarum rhizome extract in cisplatin-treated rats with hepatocellular carcinoma

This study was conducted to estimate the preventing and sensitizing efficiency of Alpinia officinarum rhizome extract (AORE) in an experimental model of hepatocellular carcinoma (HCC) +/− cisplatin. HCC was induced by a single intraperitoneal (i.p) dose of diethylnitrosamine (DENA, 200mg/kg). After 14 days, phenobarbitone (PB, 0.05%) was added to drinking water for 14 weeks to promote hepatocarcinogenesis. Cisplatin (CP) was given in a dose of 1.5 mg/kg (i.p), twice a week, alone or with AORE (400 mg/kg daily, orally) for 21 days. AORE was tried as a protective before the induction of HCC for three weeks as well. Results revealed that DENA/PB elevated hepatic indices as ALT and AST and total bilirubin with declining serum total protein. It increased oxidative stress, as hepatic malondialdehyde (MDA) with depressed hepatic reduced glutathione (GSH) contents, superoxide dismutase (SOD) and catalase activities. This was accompanied by an increase in hepatic expression of antioxidant genes (thioredoxin and glutaredoxin). Hepatocarcinogenesis was detected by histopathological changes in liver sections and the elevation of serum alpha-fetoprotein (AFP) level. Treatment with CP partially restored altered hepatic functions and oxidative stress markers. It also showed a partial decrease in the expression of antioxidant genes, improving histopathological changes in the liver and AFP level in serum. The treatment with AORE alone or AORE+CP enhanced hepatic function and oxidative stress markers. It also caused a decrease in the expression of antioxidant genes and improved histopathological changes in liver and serum AFP level. This effect is more potent than the treatment with CP alone. Our study suggested that AORE can be used as a promising natural chemoprevention or a chemosensitizing agent against hepatocarcinogenesis.

Anti-tumor activity of phloretin in treatment of induced hepatocellular carcinoma in rats.

Background: Hepatocellular carcinoma (HCC) is a major health problem, classified among the higheast five most widespread malignancies. Objectives: this experimental study aims to assess the anti-tumor activity of phloretin in treatment of induced HCC in rats. Methods: fifty adult male albino rats were classified into 5 groups (n=10, each). Group I (control group), Group II (DMSO group). Group III (preventive) (pre-treated with phloretin for 14 day before HCC induction and continued during induction period) .Group IV was HCC – Induced (DENA) group. Group V (therapeutic group) (treated with phloretin after HCC induction peroid). At the end of the experiment blood serum samples and liver tissues were collected. Results: the results showed that DENA caused liver damage as proved by significant high increase in (ALT), (AST), (ALP) (GGT) activities and marked significant decrease in albumin content. Also, induced oxidative stress as pointed out an increase in (MDA) and (NO) level and decrease in (GSH), (GST) and (CAT) activity compared with the control values. Also, it decreased apoptotic pathway by decrease in Caspase-3 and Caspase-8 concentration. Treatment with phloretin significantly reduced the elevation in liver enzymes and oxidative stress; it also induced apoptosis by significant increase in Caspase-3 and Caspase-8 concentration compared to HCC group. Conclusions: this study suggests that phloretin plays an important role in protection against DENA induced HCC.

Novel mutations in transthyretin gene associated with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the major health problems with increasing incidence worldwide. We report the elevation in transthyretin (TTR) expression following HCC induction using diethylnitrosamine (DEN) and 2-aminoacetylfluorine (2-AAF) in male Wistar rats. The increase in its expression took place at very early stage and remained elevated throughout HCC progression. The analysis of TTR gene in HCC bearing rats revealed four novel mutations that alter three amino acids at positions 61, 100, and 115. While these mutations do not directly affect the binding of TTR to thyroxine (T4 ), the mutation in amino acid 115 interferes with TTR tetramer formation that leads to its accumulation. Further, the mutated TTR is unable to cleave C-terminal of apolipoprotein A1 (APOA1) that results in abnormal lipid metabolism. This has correlation with development of liver cirrhosis and HCC. Furthermore, the mutated TTR seems to have potential as biomarker for early detection of HCC.

Therapeutic effect of carnosine in rat model of experimental liver carcinogenesis

The possible anticancer effect of carnosine versus doxorubicin was investigated against hepatocellular carcinoma (HCC) induced by trichloroacetic acid (TCA) (500mg/kg/day, p.o., for 5days) in rats. Following induction of HCC, rats treated with either carnosine (10mg/kg/day, i.p.), or doxorubicin (2.5mg/kg, i.p., once weekly), for 2 weeks. Carnosine significantly decreased serum alanine aminotransferase, and hepatic lipid peroxidation, nitric oxide, tumor necrosis factor-α, and nuclear factor-κB p65 unit, and significantly increased liver total antioxidant status in TCA-challenged rats. The effects of doxorubicin on oxidative, nitrative, and inflammatory biomarkers were less significant than carnosine. However, both carnosine and doxorubicin significantly induced liver tissue apoptotic biomarkers, Bax, cytosolic cytochrome C, and caspase-3, in a comparable manner. Additionally, carnosine and doxorubicin reduced the histopathological dysplastic changes, and alpha-fetoprotein expression in liver of rats with HCC. It was concluded that carnosine significantly protected against TCA-induced liver carcinogenesis in rats, through its antioxidant, antinitrative, and anti-inflammatory effects, and induction of apoptosis.

Umbelliferon-α-d-glucopyranosyl-(2I → 1II)-α-Dglucopyranoside ameliorates Diethylnitrosamine induced precancerous lesion development in liver via regulation of inflammation, hyperproliferation and antioxidant at pre-clinical stage

It is well documented that anomalous production of inflammatory proteins linked with most of the toxic expression and genesis of diverse chronic disease including cancer. Diethylnitrosamine (DEN) a well-known hepatotoxin and hepatocarcinogen, can induce oxidative stress and inflammatory reaction in it. Umbelliferone, secondary metabolites, is present in different plants and widely consumed by humans as medicine and food supplements. The aim of the current study was to scrutinize the chemoprotective potential of umbelliferon-α-d-glucopyranosyl-(2I→1II)-α-d-glucopyranoside (UFD) against DEN-induced hepatocellular carcinoma (HCC) in experimental rats. Single intraperitoneal injection of DEN (200mg/kg) was used for induction of HCC in rats and rats were grouped and orally treated with UFD (5, 10 and 20mg/kg) dose for 22 weeks. Parameters under investigation included hepatic, non-hepatic enzymes, oxidative stress, pro-inflammatory cytokines, COX-2 and NF-κB level along with histopathological examination in HCC rats. UFD exerted protective effect via reduction of oxidative stress, liver and non-liver parameters in a dose-dependent manner. It also reduced the expression of TNF-α, IL-1β, IL-6 and COX-2 in diseased rats. Our result revealed the essential repression of the inflammation cascade through modulation of nuclear factor-kappa B (NF-κB) signaling pathway.

Novel 1,2,4-triazole derivatives as antitumor agents against hepatocellular carcinoma

Fifteen novel 1,2,3-triazole derivatives were prepared in series of synthetic steps starting from 4-amino-5-hydrazino-4H-1,2,4-triazole-3-thiol 1. The structures of the obtained compounds were verified through micoanalytical and spectral data. All the compounds were screened for their anticancer activity against liver human cancer cell lines (HEPG2) using Doxorubicin as standard. The most promising triazolothiadiazine derivative 12 was further tested for its degree of toxicity by estimating the median lethal dose (LD 50) and its antitumor activity through inhibiting the angiogenesis and progression of tumor against diethylnitrosamine (DENA)/CCl4 induced hepatocellular carcinoma (HCC) in rats. To elucidate its mechanism of action, the following parameters were determined including: vascular endothelial growth factor (VEGF) as a marker of angiogenesis; hepatic tyrosine kinase (HTK) as a marker for tumor growth; serum alpha fetoprotein (AFP) as a marker for hepatocarcinoma; aspartate and alanine aminotransferases (AST & ALT) as liver function test; malondialdehyde (MDA) and glutathione (GSH) as markers of antioxidant activity. Liver histopathological analysis was also evaluated. Carcinogenic rats showed drastic elevation in all investigated parameters accompanied by reduction in hepatic glutathione. Administration of compound 12 into rats after induction of experimental HCC, improved the biochemical changes induced by DENA/CCl4. These observations were supported by histopathological study of liver sections. It was concluded that triazolothiadiazine compound 12 could be promising anti HCC agent after more investigations on higher animals.

An insight on the association of glycation with hepatocellular carcinoma.

Hepato-cellular carcinoma (HCC) is one of the frequent cause of cancer-related death worldwide and dominant form of primary liver cancer. However, the reason behind a steady increase in the incidence of this form of cancer remains elusive. Glycation has been reported to play a significant role in the induction of several chronic diseases including cancer. Several risk factors that could induce HCC have been reported in the literature. Deciphering the complex patho-physiology associated with HCC is expected to provide new targets for the early detection, prevention, progression and recurrence. Even-though, some of the causative aspects of HCC is known, the advanced glycation end products (AGEs) related mechanism still needs further research. In the current manuscript, we have tried to uncover the possible role of glycation in the induction of HCC. In the light of the available scientific literature, we advocate in-depth comprehensive studies which will shed light towards mechanistic association of glycation with HCC.