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Scope: Prunus avium fruit is the richer source of phenolics known to exert anticancer and anti-invasive activities. The study aimed at elucidating antiproliferative and chemo-preventive potential of sweet cherries ( P. avium ) against the in vivo hepatocarcinoma model., Methods and Results: The quantification of ultrasound-assisted extract (UAE) of P. avium depicted anthocyanins, ferulic acid, gallic acid, quercetin, syringic acid and p- and m-coumaric acids as major phytochemicals. The hepatocarcinoma (HCC) was induced in rats through intraperitoneal administration of DMBA (20 mg/kg B.W) once a week for the period of eight weeks. The intragastric administration of P. avium UAE, as cotreatment (500 mg/Kg B.W) to treatment group, significantly ( p  < 0.01) attenuated the raised serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) as well as total oxidative stress (TOS) and enhanced total antioxidant capacity TAOC in contrast to diseased rats. Moreover, microscopic examination of hepatic tissues confirmed the pleomorphism, nests of neoplastic hepatocytes and necrosis in HCC-bearing rats as compared to extract-fed rats, where these necrotic changes were suppressed. Besides, qRT-PCR analysis of hepatic tissues demonstrated the higher mRNA expression of CHEK1, CHEK2 and P21/CDKN1α genes, while downexpression of ATM gene in extract fed rats, further denoting the anti-mutagenic potential., Conclusion: Consequently, the polyphenol-rich sweet cherries UAE exhibited antiproliferative and chemo-preventive potential by reducing tumor biomarkers, serum transaminases and oxidative stress, as well as enhancing antioxidant status. It further upregulated the downstream targets of ATM signaling cascade., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saeed, Khan, Butt and Faisal.)

Hepatocellular carcinoma is the most common primary malignant hepatic tumor and occurs most often in the setting of chronic liver disease. Liver transplantation is a curative treatment option and is an ideal solution because it solves the chronic underlying liver disorder while removing the malignant lesion. However, due to organ shortages, this treatment can only be applied to carefully selected patients according to clinical guidelines. Artificial intelligence is an emerging technology with multiple applications in medicine with a predilection for domains that work with medical imaging, like radiology. With the help of these technologies, laborious tasks can be automated, and new lesion imaging criteria can be developed based on pixel-level analysis. Our objectives are to review the developing AI applications that could be implemented to better stratify liver transplant candidates. The papers analysed applied AI for liver segmentation, evaluation of steatosis, sarcopenia assessment, lesion detection, segmentation, and characterization. A liver transplant is an optimal treatment for patients with hepatocellular carcinoma in the setting of chronic liver disease. Furthermore, AI could provide solutions for improving the management of liver transplant candidates to improve survival.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with high morbidity and mortality, which seriously threatens the health and life expectancy of patients. The traditional methods of treatment by surgical ablation, radiotherapy, chemotherapy, and more recently immunotherapy have not given the expected results in HCC. New integrative combined therapies, such as photothermal, photodynamic, photoimmune therapy (PTT, PDT, PIT), and smart multifunctional platforms loaded with nanodrugs were studied in this review as viable solutions in the synergistic nanomedicine of the future. The main aim was to reveal the latest findings and open additional avenues for accelerating the adoption of innovative approaches for the multi-target management of HCC. High-tech experimental medical applications in the molecular and cellular research of photosensitizers, novel light and laser energy delivery systems and the features of photomedicine integration via PDT, PTT and PIT in immuno-oncology, from bench to bedside, were introspected. Near-infrared PIT as a treatment of HCC has been developed over the past decade based on novel targeted molecules to selectively suppress cancer cells, overcome immune blocking barriers, initiate a cascade of helpful immune responses, and generate distant autoimmune responses that inhibit metastasis and recurrences, through high-tech and intelligent real-time monitoring. The process of putting into effect new targeted molecules and the intelligent, multifunctional solutions for therapy will bring patients new hope for a longer life or even a cure, and the fulfillment of the myth of Prometheus.

Extracellular vesicles (EVs) are cell-derived membrane structures that are formed by budding from the plasma membrane or originate from the endosomal system. These microparticles (100 nm-100 µm) or nanoparticles (>100 nm) can transport complex cargos to other cells and, thus, provide communication and intercellular regulation. Various cells, such as hepatocytes, liver sinusoidal endothelial cells (LSECs) or hepatic stellate cells (HSCs), secrete and take up EVs in the healthy liver, and the amount, size and content of these vesicles are markedly altered under pathophysiological conditions. A comprehensive knowledge of the modified EV-related processes is very important, as they are of great value as biomarkers or therapeutic targets. In this review, we summarize the latest knowledge on hepatic EVs and the role they play in the homeostatic processes in the healthy liver. In addition, we discuss the characteristic changes of EVs and their potential exacerbating or ameliorating effects in certain liver diseases, such as non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), drug induced liver injury (DILI), autoimmune hepatitis (AIH), hepatocarcinoma (HCC) and viral hepatitis.

En México se ha detectado la presencia AFB1 en humanos: como mutación en el gene p53 en hepatocarcinomas de pacientes de Monterrey, Nuevo León, México, en 1996 y como aducto AFB1-lisina en suero de pacientes del Instituto Mexicano del Seguro Social de Matamoros, Tamaulipas, México, en 2003. La aflatoxina B1 ha sido clasificada por la Agencia Internacional para Investigación en Cáncer como un agente carcinogénico para humanos. Este compuesto es un contaminante natural encontrado en alimentos y es sintetizado por Aspergillus flavus y/o A. parasiticus cuando estos hongos crecen en diversos productos alimenticios. Considerando el riesgo que este compuesto representa para los seres humanos, en el presente artículo se revisa y analiza, a nivel molecular, su capacidad carcinogénica, mutagénica y tóxica y se ilustra su relación causal con hepatocarcinomas en humanos. Se destaca que la capacidad carcinogénica y mutagénica están determinadas por la AFB1-formamidopirimidina, la cual causa errores en las transcripciones del ADN. Los resultados ilustran que la población mexicana está consumiendo alimentos con bajas concentraciones de AFB1. La toxicidad es consecuencia de la acción carcinogénica en el hígado.The presence of AFB1 in human beings was detected in Mexico in 1996 both as a mutation of the gene p53 in hepatocellular carcinomas in Monterrey, Mexico, and as the adduct AFB1-lysine in serum from patients in Matamoros, Mexico in 2003. Aflatoxin B1 has been classified as a carcinogenic agent to humans by the International Agency for Research on Cancer. The compound is a natural contaminant produced by Aspergillus flavus and/or A. parasiticus when these fungi grow on different food products. At the molecular level, this review covers the carcinogenic, mutagenic and toxic properties of these mycotoxins and their risk to humans. It also gives insight into the causal relationship between aflatoxins and hepatocellular carcinoma. Information is provided about AFB1-formamidopyrimidine, which is a determinant of the carcinogenic and mutagenic capabilities. The results suggest that the Mexican population ingests food containing low amounts of AFB1. Analyses is presented of AFB1 toxicity, which is a consequence of the carcinogenic activity in liver cells.

Objetivo: el objetivo de nuestro estudio fue valorar en nuestro medio las características clínicas, ecográficas y evolutivas de los pacientes con hepatopatía crónica y lesiones ecográficas sugestivas de angiomas hepáticos. Material y métodos: estudio retrospectivo realizado entre los pacientes recogidos en la base de datos de la Unidad de Ecografías del Servicio de Aparato Digestivo entre enero de 2000 y junio de 2004. Incluimos en el estudio a pacientes que presentaban datos clínicos y/o analíticos compatibles con hepatopatía crónica de cualquier etiología y en los que la ecografía abdominal ponía de manifiesto la existencia de al menos una lesión hepática compatible con angioma. Se han recogido los datos epidemiológicos, clínicos, ecográficos y evolutivos de estos pacientes. Resultados: durante el periodo de estudio se diagnosticaron 58 pacientes con hepatopatía crónica y lesiones hepáticas sugestivas de angioma, de los cuales trece presentaban datos clínicos, analíticos, ecográficos y/o histológicos compatibles con cirrosis hepática. Ecográficamente se trataban de lesiones menores de 10 mm en el 50% de los pacientes y en la mayoría de los casos localizadas en lóbulo hepático derecho. Durante el periodo de medio de 35 meses (6 a 168 meses) se pudo comprobar cómo en dos pacientes (3%) las lesiones inicialmente interpretadas como angiomas se trataban en realidad de lesiones malignas (un hepatocarcinoma y unas metástasis de adenocarcinoma vesicular). En ambos casos los pacientes eran cirróticos. Por tanto, en el 15% de los pacientes cirróticos de nuestra serie se demostró la naturaleza maligna de las lesiones inicialmente interpretadas como angiomas. Conclusiones: en pacientes con hepatopatía crónica, sobre todo en cirróticos, un porcentaje no despreciable de las lesiones ecográficas interpretadas inicialmente como angiomas se tratan realmente de lesiones malignas.Objective: the aim of this study was to evaluate in our healthcare area the clinical, ultrasonographic, and evolutionary features of patients with chronic liver disease and angioma-like liver lesions on ultrasonography. Materials and methods: we conducted a retrospective study amongst patients seen at the Ultrasonography Unit, Gastroenterology Department between January 2000 and June 2004. Included in the study were patients that presented with clinical and/or laboratory complaints consistent with chronic liver disease of any etiology, and those in which abdominal ultrasounds revealed the existence of at least one angioma-like liver lesion. All relevant epidemiological, clinical, ultrasonographic, and evolutionary data were carefully collected and recorded. Results: in the course of our study, 58 patients were diagnosed with chronic liver disease and angioma-like liver lesions, of which 13 showed clinical, laboratory, ultrasonographic, and/or histological signs of liver cirrhosis. In 50% of patients these lesions were less than 10 mm in diameter, and in most cases were located in the right hepatic lobe. During an average follow-up period of 35 months (6-168 months) we verified that, in two patients, these lesions, initially interpreted as angiomas were in fact malignancies (one hepatocellular carcinoma and one metastatic adenocarcinoma of the gallbladder). In both cases, the patients were cirrhotic. Thus, our study revealed that 15% of lesions found in cirrhotic patients initially interpreted as angiomas were actually malignant. Conclusions: our study revealed that, in patients with chronic liver disease, particularly in cirrhotic patients, a considerable percentage of ultrasonographic lesions originally interpreted as angiomas are in fact malignant tumors.

Liver cancer is themost endemic cancer in a large region of theworld. This study investigated the anti-metastatic effects of an extract of Monascus purpureus CWT715 (MP) fermented from sorghum liquor biowaste and its mechanisms of action in highly metastatic human hepatocarcinoma SK-Hep-1 cells. Kinmen sorghum liquor waste was used as the primary nutrient source to produce metabolites (including pigments) of MP. In the presence of 10 μg/mL MP-fermented broth (MFB), the anti-invasive activity increased with increasing fermentation time reaching a maximum at six days of fermentation. Interestingly, MFB also produced maximal pigment content at six days. Treatment for 24 h with MFB (10-100 μg/mL) obtained from fermentation for six days significantly inhibited cell migration and invasion, and these effects were concentration-dependent. MFB also significantly enhanced nm23-H1 protein expression in a concentration-dependent manner, which was highly correlated with migration and invasion. These results suggest that MFB has significant anti-migration and anti-invasion activities and that these effects are associated with the induction of nm23-H1 protein expression. [ABSTRACT FROM AUTHOR]

The mouse hepatocarcinoma cell lines Hca-F and Hca-P have been derived from hepatocarcinoma in mice and metastasize only to the lymph node. Hca-F cells displayed greater lymphatic metastasis ability than Hca-P cells. When the two cell lines were compared for cell surface sialylated β1,6 branched N-glycans by flow cytometry using L-PHA and SNA, Hca-F cells were found to express significantly higher levels. To explore the effect of increased sialylated β1,6 branched N-glycans on hepatocarcinoma progression, we inhibit their expression in Hca-F cells by using swainsonine treatment and RNA interference. We found that swainsonine treatment or GnT-V-shRNA transfection significantly inhibited the formation of β1,6 branched N-glycans, and partially inhibited the expression of α2,6 sialic acids. Knockdown of sialylated β1,6 branched N-glycans significantly attenuated the invasive and metastatic capability both in vitro and in vivo . Blockade of α2,6 sialic acid expression on Hca-F cell surface by the treatment with neuraminidase caused reduction in cellular adherence to lymph node. In addition, knockdown of sialylated β1,6 branched N-glycans could decrease the expression of Notch1, NICD1, NICD2 and HES1 in Hca-F cells. Collectively, these findings suggest that increased sialylated β1,6 branched N-glycans may contribute to hepatocarcinoma progression by altering the adhesive, invasive and metastatic ability to lymph node via Notch signaling pathway. [ABSTRACT FROM AUTHOR]

Objective Annexin A5 (Anxa5) is associated with the progression of some cancers, while its role and regulation mechanism in tumor lymphatic metastasis is rarely reported. This study aims to investigate the influence of Anxa5 knockdown on the malignant behaviours of murine hepatocarcinoma Hca-F cell line with high lymph node metastatic (LNM) potential and the underlying regulation mechanism. Methods RNA interfering was performed to silence Anxa5 in Hca-F. Monoclonal shRNA-Anxa5- Hca-F cells were obtained via G418 screening by limited dilution method. Quantitative real-time RT-PCR (qRT-PCR) and Western blotting (WB) were applied to measure Anxa5 expression levels. CCK-8, Boyden transwell-chamber and in situ LN adhesion assays were performed to explore the effects of Anxa5 on the proliferation, migration, invasion and adhesion capacities of Hca-F. WB and qRT-PCR were used to detect the level changes of key molecules in corresponding signal pathways. Results We obtained two monoclonal shRNA-Anxa5-transfected Hca-F cell lines with stable knockdowns of Anxa5. Anxa5 knockdown resulted in significantly reduced proliferation, migration, invasion and in situ LN adhesion potentials of Hca-F in proportion to its knockdown extent. Anxa5 downregulation enhanced E-cadherin levels in Hca-F. Moreover, Anxa5 affected Hca-F behaviours specifically via ERK2/p-ERK2/c-Jun/p-c-Jun(Ser73) instead of p38MAPK/c-Jun, Jnk/c-Jun and AKT/c-Jun pathways. Conclusions Anxa5 mediates the in vitro malignant behaviours of murine hepatocarcinoma Hca-F cells via ERK2/c-Jun/p-c-Jun(Ser73) and ERK2/E-cadherin pathways. It is an important molecule in metastasis (especially LNM) and a potential therapeutic target for hepatocarcinoma. [ABSTRACT FROM AUTHOR]

Alterations in mitochondrial DNA (mtDNA) and autophagy activation are common events in tumors. Here we have investigated the effect of mitochondrial genome depletion on chemical hypoxia-induced autophagy in liver tumor cells. Human SK-Hep-1 wild-type and mtDNA-depleted (Rho) cells were exposed to the hypoxia mimetic agents CoCl 2 and deferoxamine (DFO). Up-regulation of HIF-1α, but not HIF-2α was observed. The expression of several HIF-1α target genes was also found. In human SK-Hep-1 and mouse Hepa 1–6 liver tumor cells, but not in the counterpart Rho derived lines, chemical hypoxia increased the abundance of autophagosomes and autolysosomes. In wild-type and Rho cells, chemical hypoxia induced down-regulation of HIF-1α-dependent autophagy inhibitors Bcl-2 and mTOR, whereas activation of AMPK/ULK1-mediated pro-autophagy pathway occurred only in wild-type cells. Chemical (compound C) and genetic (shRNA) inhibition of AMPK activation resulted in reduced autophagy. ATP levels were similar in both cell types, whereas constitutive and chemical hypoxia-induced reactive oxygen species (ROS) generation was lower in Rho cells. In wild-type cells, the antioxidant N-acetylcysteine blocked CoCl 2 - and DFO-induced AMPK and autophagy activation, but not endoplasmic reticulum stress induced by CoCl 2 . Enhanced Bax-α/Bcl-2 ratio and cell death was induced by hypoxia mimetic agents more markedly in wild-type than in Rho cells. Upon blocking autophagy activation with 3-methyladenine, DFO-induced cell death was partially prevented whereas that induced by CoCl 2 was increased, but only in wild-type cells. These results suggest that mitochondrial dysfunction associated with the lack of mtDNA impairs the signaling pathways mediated by ROS, controlling autophagy activation in liver tumor cells, which may contributes to cancer development. [ABSTRACT FROM AUTHOR]

Although abnormal activation of the sonic hedgehog (Shh) signaling pathway has been demonstrated in human hepatocellular carcinoma (HCC) patients and in most HCC cell lines, the mechanism by which the Shh pathway promotes the development of HCC remains uncertain. Using a liver cancer model induced by diethylnitrosamine (DEN) which mimics the process from liver injury, abnormal hepatocyte proliferation, and hepatocirrhosis to hepatocyte canceration, we investigated the abnormal activation of the Shh pathway by examining the expression of Shh, patched-1 (Ptch), smoothened (SMO), and glioma-associated oncogene-1 (Gli1) genes. During this process, the expression of CDK1 and cyclin B1 protein, which are two components of the M-phase promoting factor (MPF) controlling G2/M transition, was also examined to explore the potential relationship between Shh activation and cell cycle progression. We observed that the cells with Shh, Ptch, and Gli1 protein expression were mainly distributed in hyperplastic nodule, cancerous node, the epithelia of interlobular bile duct, and precancerous tissues. A gradually increasing tendency of the positive expression rate of Shh, Ptch, and Gli1 proteins in the process from the beginning normal tissue to the final cancer formation was revealed. The cyclin B1 and CDK1 expression level was higher in the DEN-induced rats as compared with normal rats, and their expression was mainly distributed in the portal area of the liver, hyperplastic nodule, cancerous node, and precancerous tissues. Our results suggested that the Shh signaling pathway is activated during liver carcinogenesis, and activated Shh signaling promotes the cell proliferation by facilitating the G2/M transition through increasing the expression of cyclin B1 and CDK1 protein, which eventually results in the development of liver cancer. Better understanding of the Shh signaling pathway in HCC may contribute to the development of novel therapeutic strategies in inhibiting cell proliferation and promoting cell cycle arrest. [ABSTRACT FROM AUTHOR]

This paper reports the case of an 86-year-old male, who presented fever and neurological impairment secondary to Listeria monocytogenes bacteremia after cycle of dexamethasone for deterioration of idiopathic thrombocytopenic purpura, diagnosed over 30 years, which has been treated over 10 years with danazol. Listeriosis is a rare disease with an incidence of 0.8/100,000 habitants and 20% mortality with treatment, observed in patients with certain state of immunosuppression as those in our patient (age, corticosteroids, diabetes mellitus). Also, in imaging tests performed by elevation of liver enzymes, we found a lesion compatible with hepatocellular carcinoma. Chronic intake of danazol was the only recognizable cause for the liver tumor. During admission patient developed hemorrhagic complications secondary to severe thrombocytopenia and concomitantly a thrombotic process with incidental finding of pulmonary thromboembolism forcing multidisciplinary management. [ABSTRACT FROM AUTHOR]

Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for treating patients with mutant KRAS resistant to other treatments. [ABSTRACT FROM AUTHOR]

Effects of sorafenib in hepatocellular carcinoma ( HCC) are frequently transient due to tumor-acquired resistance, a phenotype that could be targeted by other molecules to reduce this adaptive response. Because melatonin is known to exert antitumor effects in HCC cells, this study investigated whether and how melatonin reduces resistance to sorafenib. Susceptibility to sorafenib (10 nmol/L to 50 μmol/L) in the presence of melatonin (1 and 2 mmol/L) was assessed in HCC cell lines HepG2, HuH7, and Hep3B. Cell viability was reduced by sorafenib from 1 μmol/L in HepG2 or HuH7 cells, and 2.5 μmol/L in Hep3B cells. Co-administration of melatonin and sorafenib exhibited a synergistic cytotoxic effect on HepG2 and HuH7 cells, while Hep3B cells displayed susceptibility to doses of sorafenib that had no effect when administrated alone. Co-administration of 2.5 μmol/L sorafenib and 1 mmol/L melatonin induced apoptosis in Hep3B cells, increasing PARP hydrolysis and BAX expression. We also observed an early colocalization of mitochondria with lysosomes, correlating with the expression of mitophagy markers PINK1 and Parkin and a reduction of mitofusin-2 and mt DNA compared with sorafenib administration alone. Moreover, increased reactive oxygen species production and mitochondrial membrane depolarization were elicited by drug combination, suggesting their contribution to mitophagy induction. Interestingly, Parkin silencing by si RNA to impair mitophagy significantly reduced cell killing, PARP cleavage, and BAX expression. These results demonstrate that the pro-oxidant capacity of melatonin and its impact on mitochondria stability and turnover via mitophagy increase sensitivity to the cytotoxic effect of sorafenib. [ABSTRACT FROM AUTHOR]

Blackgrond:plant lectins, carbohydrate binding proteins, are distributed in many species of medicinal plants mainly those belong to legumonase family. This study aimed to investigate the anticancer activity of the lectin extracted from Pisum sativum on Human Hepatocellular carcinoma (HepG2). Materials and Methods:the morphological signs of apoptosis were examined and the ability of lectin to induce alteration in both pro-apoptotic and anti-apoptotic such as Bax, IκBα, P53 and Bcl2 genes were analyzed using RT-QPCR method. The safety usage pattern of P. sativum lectin was evaluated on human HepG2 cell lines. Results: lectin displayed high antioxidant activity on the Hep2 cells when compared with 5FU (anti-cancer drug as a control). Lectin dilution that exhibits LC50 on HepG2 cells was found to touch 25% from the original concentration (100%). The extracted lectin was found with inhibition percentage in cellular viability touching 80.5% with 67.6% inhibits the integration of BrdU in the HepG2 proliferated cells. HepG2 treated cells showed apparent nuclear condensation after 16 h of treatment as lectin had the ability to upregulate the gene expression of P53 and IκBα and down regulates Bax and Bcl2. Conclusion: lectin may have a vigorous role in achievement of hepatocarcinoma therapy plan. [ABSTRACT FROM AUTHOR]

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We delineate herein the synthesis and anti-cancer effects of 15 matrine derivatives. The in vitro growth inhibitory assays showed that most of the prepared compounds exhibited improved anti-proliferative activities towards cancer cells with IC 50 17–109 times lower than that of matrine. Compounds CH6 showed the most potent anti-proliferative activities in the four tested cancer cell lines. Moreover, compound CH6 could induce G1 cell cycle arrest and inhibit cell migration in human hepatocellular cancer cell lines Bel-7402 and HepG2 through up-regulation of P21, P27 and E-cadherin and down-regulation of N-cadherin. [ABSTRACT FROM AUTHOR]

Background: The previous studies have demonstrated that the polysaccharide isolated from Tarphochlamys affinis (PTA) exhibits anti-tumor effect on S180 tumor-bearing mice and protective effects against hepatic injury. Methods: In this study, we investigated the antitumor activity and possible underlying mechanism of PTA on liver cancer using a murine H22 hepatocarcinoma model. Results: PTA was capable of repressing transplanted H22 solid hepatic tumor cell growth in vivo. The relative weight of immune organs (spleen and thymus) and lymphocyte proliferation induced by ConA or LPS were improved after PTA treatment. Furthermore, treatment with PTA promoted immune-stimulating serum cytokine secretion in H22 tumor-bearing mice. Additionally, the percentage of CD4+ T lymphocytes, CD8+ T lymphocytes and NK cells was increased in tumor-bearing mice following PTA administration. In tumor tissue, PTA significantly up-regulated the expression of Bax and p53 proteins and down-regulated the expression of Bcl-2 protein. In addition, at the therapeutic dose, PTA displayed very few toxic effects to major organs, such as the liver and kidney, in tumor-bearing mice. Conclusion: In H22 tumor-bearing mice, PTA exhibited prominent anti-tumor activity in vivo. The possible mechanism of action might be related to enhanced host immune system function and induction of H22 tumor cell apoptosis. [ABSTRACT FROM AUTHOR]

ST6GalNAc I is the major Sialyl-Tn antigen (STn) synthase that is highly correlated with tumor invasion and metastasis. However, the roles and molecular mechanisms by which ST6GalNAc I mediates the malignant phenotypes of hepatocarcinoma cells still remain poorly unknown. In this study, we investigated the expression of STn and ST6GalNAc I in mouse hepatocarcinoma cell lines Hca-F, Hca-P, and Hepa1-6, which have different metastatic potential, as compared with normal mouse liver cell line IAR-20. The results showed that the expression of ST6GalNAc I and STn in Hca-F and Hca-P cells was much higher than that in Hepa1-6 and IAR20 cells. Knockdown of ST6GalNAc I by shRNA in Hca-F cells significantly decreased the expression of STn and inhibited the growth of tumor cells in vitro and in vivo. This reduction of ST6GalNAc I expression also led to the decreased migration and invasion of Hca-F cells. Furthermore, we found that ST6GalNAc I knockdown inhibited the expression levels of PI3k, p-Akt473, p-Akt308, NF-κB, and their downstream molecules. Together, our results suggest a role of ST6GalNAc I in promoting the growth and invasion of hepatocarcinoma cells through regulating PI3K/AKT signaling, and ST6GalNAc I might be a promising marker for the prognosis and therapy of hepatocarcinoma. [ABSTRACT FROM AUTHOR]

Toxicity of the SYD-1 mesoionic compound (3-[4-chloro-3-nitrophenyl]-1,2,3-oxadiazolium-5-olate) was evaluated on human liver cancer cells (HepG2) grown in either high glucose (HG) or galactose (GAL) medium, and also on suspended cells kept in HG medium. SYD-1 was able to decrease the viability of cultured HepG2 cells in a dose-dependent manner, as assessed by MTT, LDH release and dye with crystal violet assays, but no effect was observed on suspended cells after 1–40 min of treatment. Respiration analysis was performed after 2 min (suspended cells) or 24 h (cultured cells) of treatment: no change was observed in suspended cells, whereas SYD-1 inhibited as well basal, leak and uncoupled states of the respiration in cultured cells with HG medium. These inhibitions were consistent with the decrease in pyruvate level and increase in lactate level. Even more extended results were obtained with HepG2 cells grown in GAL medium where, additionally, the ATP amount was reduced. Furthermore, SYD-1 appears not to be transported by the main ABC multidrug transporters. These results show that SYD-1 is able to change the metabolism of HepG2 cells, and suggest that its cytotoxicity is related to impairment of mitochondrial metabolism. Therefore, we may propose that SYD-1 is a potential candidate for hepatocarcinoma treatment. [ABSTRACT FROM AUTHOR]

Objective: It approached the cause, prevention and cure of the hemorrhage after hepatocarcinoma cryoablation in this paper. Design: The study was finished in Department of Neurosurgery, Wuhan General Hospital of Guangzhou Military Command of Chinese PLA, Wuhan 430070, Hubei Province, China. I promise that the study was performed according to the international, national and institutional rules considering clinical studies and biodiversity rights. Methods: It analyzed 487 clinical data of the cryoablation for hepatocarcinoma from October 1999 to January 2011, with 402 data guided by percutaneous ultrasound or CT, 85 by oculus; According to signs and symptoms of the patients, correlation factors of hemorrhage of clinical analysis, the volume of hemorrhage, and whether there is complicated bleeding judged by ultrasound, angiography, and abdominal paracentesis. It used vein medicine addition partly compression (32), intervention embolism (14) and surgical procedures (5) for Hemostasis. Results: 487 hepatocarcinoma sufferers treated by cryoablation, with 51 (10.5%) bleeding, 39 happened during the treatment, 12 happened after the therapy, 49 with successful hemostasis and 2 dead. Analytic result of hemorrhage shows that there are some evocations, such as affiliate cirrhosis of liver (p = 0.030), prothrombin time elongation (p = 0.030), thrombocytopenia (p = 0.024), neoplasms located under liver capsule (p = 0.043), the size of cryoprobe is too big (P= 0.003) and too many puncture (P = 0.025), which evokes hemorrhage easily. By vein hemostasis + compression hemostasis (31), intervention embolism (13) and surgical procedures (5), hemostasis can be successful after bleeding. Conclusion: Hepatocarcinoma cryoablation complicating hemorrhage has highly risk, which often happens in Peroperative Period, and has significant associativity with hepatic cirrhosis, prothrombin time lengthen, thrombocytopenia, neoplasms is located under liver capsule or not, thick cryoprobe and too much puncture; So indication should be controlled strictly, and doctor should have high precaution if hemorrhagic tendency appears, ones bleeding happens, It must be correctly judged and given suitable treatment. [ABSTRACT FROM AUTHOR]

The side-effects observed in conventional therapies have made them unpromising in curing Hepatocellular carcinoma; therefore, developing novel treatments can be an overwhelming significance. One of such novel agents is curcumin which can induce apoptosis in various cancerous cells, however, its poor solubility is restricted its application. To overcome this issue, this paper employed dendrosomal curcumin (DNC) was employed to in prevent hepatocarcinoma in both RNA and protein levels. Hepatocarcinoma cells, p53 wild-type HepG2 and p53 mutant Huh7, were treated with DNC and investigated for toxicity study using MTT assay. Cell cycle distribution and apoptosis were analyzed using Flow-cytometry and Annexin-V-FLUOS/PI staining. Real-time PCR and Western blot were employed to analyze p53, BAX, Bcl-2, p21 and Noxa in DNC-treated cells. DNC inhibited the growth in the form of time-dependent manner, while the carrier alone was not toxic to the cell. Flow-cytometry data showed the constant concentration of 20 μM DNC during the time significantly increases cell population in SubG1 phase. Annexin-V-PI test showed curcumin-induced apoptosis was enhanced in Huh7 as well as HepG2, compared to untreated cells. Followed by treatment, mRNA expression of p21, BAX, and Noxa increased, while the expression of Bcl-2 decreased, and unlike HepG2, Huh7 showed down-regulation of p53. In summary, DNC-treated hepatocellular carcinoma cells undergo apoptosis by changing the expression of genes involved in the apoptosis and proliferation processes. These findings suggest that DNC, as a plant-originated therapeutic agent, could be applied in cancer treatment. [ABSTRACT FROM AUTHOR]

Lactate dehydrogenase (LDH) is a terminal enzyme in anaerobic glycolytic pathway. It widely exists in various organisms and is in charge of converting the glycolysis product pyruvic acid to lactic acid. Most parasites, including Clonorchis sinensis, predominantly depend on glycolysis to provide energy. Bioinformatic analysis predicts that the LDHs from many species have more than one transmembrane region, suggesting that it may be a membrane protein. C. sinensis LDH (CsLDH) has been confirmed as a transmembrane protein mainly located in the tegument. The antibodies against CsLDH can inhibit the worm's energy metabolism, kill the worm, and may have the same effects on human cancer cells. In this study, we cloned and characterized human LDHA (HsLDHA), HsLDHB, and CsLDH. Semi-quantitative real-time RCP showed that HsLDHB only existed in hepatocarcinoma cell SMMC-7721. Confocal microscopy and Western blot experiments revealed that HsLDHB was localized in the plasma membrane of SMMC-7721 cells, and the antibodies against CsLDH could cross-react with it. This cross-reaction could inhibit the enzymatic activity of HsLDHB. The cancer cells co-cultured with anti-CsLDH sera showed a significant decrease in cell proliferation rate and increases in caspase 9 and reactive oxygen species (ROS) levels. Therefore, anti-CsLDH antibodies can induce the apoptosis of cancer cells SMMC-7721 and may serve as a new tool to inhibit tumor. [ABSTRACT FROM AUTHOR]

Purpose This study was conducted to evaluate the biological features of murine hepatocarcinoma according to different tumor microenvironmental models and to determine the change in molecular and immunologic responses after radiation. Materials and Methods Tumor models were established in the liver (orthotopic) and thigh (heterotopic) of male C3H/HeN mice. Tumor growth and lung metastasis were assessed in these models. To evaluate the radiation effect, the tumors were irradiated with 10 Gy. Factors associated with tumor microenvironment including vascular endothelial growth factor (VEGF), cyclooxygenase- 2 (COX-2), transforming growth factor beta1 (TGF-β1), CD31, and serum interleukin- 6 (IL-6) were evaluated. Tumor-infiltrating regulatory immune cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) were also analyzed. Results A higher number of lung metastases were observed in the orthotopic tumor model than in the heterotopic tumor model. VEGF, CD31, COX-2, and TGF-β1 expression was more prominent in the orthotopic tumor model than in the heterotopic tumor model. Expression of the angiogenic factor VEGF and key regulatory molecules (TGF-β1 and COX-2) decreased following radiation in the orthotopic tumor model, while the serum IL-6 level increased after radiation. In the orthotopic tumor model, the number of both Tregs and MDSCs in the tumor burden decreased after radiation. Conclusion The orthotopic tumor model showed higher metastatic potential and more aggressive molecular features than the heterotopic tumor model. These findings suggest that the orthotopic tumor mouse model may be more reflective of the tumor microenvironment and suitable for use in the translational research of radiation treatment. [ABSTRACT FROM AUTHOR]

Purpose: Interactions between endothelial and tumor cells via E-selectin and sialyl Lewis x (sLex) have been suggested to play a significant role in the development of metastasis and tumor growth. In this work, we tested whether inhibition of E-selectin expression on the surface of endothelial cells might impair endothelial/tumor cells interactions and tumor growth of hepatocarcinoma cells in vitro and in vivo.Methods: We used HepG2 cells that highly express sLex antigens and HuH7 cells that do not express sLex. Inhibition of E-selectin expression on the surface of endothelial cells was obtained by using cimetidine and amiloride treatment.Results: Cimetidine and amiloride inhibited, respectively, by 20 and 64 % E-selectin expression by activated endothelial cells and significantly subsequent adhesion of HepG2 cells to activated endothelial cells. Subcutaneous injection of cimetidine or amiloride resulted in a significant inhibition of HepG2 cells tumor growth in nu/nu mice but not of HuH7 cells. Thus, cimetidine and amiloride administration led to an inhibition of 57 and 75 % of HepG2 tumor growth in vivo, respectively. This effect was associated with an inhibition of vasculogenesis as demonstrated by anti-CD31 immunostaining.Conclusion: Inhibition of E-selectin expression allows an anti-tumoral effect on sLex-expressing HCC tumors in vivo. This suggests that interactions between HCC cells and endothelial cells through sLex antigens and E-selectin might be a target for treatment of HCC. Further studies might evaluate the clinical impact of cimetidine and amiloride in the treatment of HCC patients alone or in combination with other anti-tumoral agents. [ABSTRACT FROM AUTHOR]

We unveiled the association of Annexin A7 with vascular endothelial growth factor-C (VEGF-C) and the effect of upregulation of Annexin A7 in Hca-F and Hca-P cells on inhibiting hepatocarcinoma (HCC) lymph node metastasis (LNM) in vitro and in vivo. A total of 200 inbred 615 mice were randomly divided into four equal groups inoculated with Hca-F, Hca-P, F, and P cells, respectively. The primary tumor, popliteal, inguinal, and iliac lymph nodes were prepared for immunohistochemical (IHC) staining, real-time quantitative polymerase chain reaction (qRT-PCR) analysis, Western blot, and hematoxylin-eosin (H&E) staining. There was over 50 % increase both in the number of F and P cells migrated through the filter compared to their controls (F, Hca-F and P, Hca-P). However, no significant differences were noted in invasion ability between them (all P > 0.05). Tumor lymph vessels were significantly reduced in F and P tumors when compared with Hca-F and Hca-P tumors (all P < 0.05). Blood vessel density did not differ significantly between F and P tumors and Hca-F and Hca-P tumors. Enzyme-linked immunosorbent assay (ELISA) for VEGF-C showed that upregulating Annexin A7 decreased VEGF-C secretion in F and P cells ( P < 0.05). The IHC staining result showed that the level of serum Annexin A7 was found to be statistically higher in all experimental groups than that in the control group ( P < 0.05). The present results indicated that alterations in serum Annexin A7 expression may be of prognostic relevance in HCC lymphatic metastasis. [ABSTRACT FROM AUTHOR]

Objective: hepatocellular carcinoma (HCC) ablation by radiofrequency (RFA) is a novel technique with a great variety of methods whose efficacy and predictive factors have not been completely studied. Some of the main predictive factors in this type of treatment are analyzed in the present study. Patients and methods: ninety-three patients with hepatocellular carcinoma over cirrhosis, and with no indication for surgical resection were treated by RFA. Two different types of electrodes were used for RFA (refrigerated-"Cool-Tip" and perfusion with saline solution, the approach was percutaneous, by laparoscopy or laparotomy. Results: overall survival at 1, 2 and 3 years was 88, 81, and 76%, with a free-disease survival (FDS) of 66, 31 and 17%, respectively. For tumors less than 3 cm, FDS at 1,2 and 3 years was 74, 44 and 30%, while for more than 3 cm in size FDS was 55, 12 and 0% (p = 0.02). FDS for HCC with one nodule was 70, 36 and 22%, and for more than one nodule it decreased to 50, 17 and 0% at 1, 2 and 3 years, respectively (p = 0.07). Surprisingly, the method employed for RFA has a main influence in FDS, with 0% at 3 years for perfusion electrodes and 26% for cool-tip electrodes at the same period. Conclusions: in this series, overall survival at three years was relatively high; however, tumoral size, number of nodules and RFS method were independent variables associated with disease-free survival.Objetivo: la ablación por radiofrecuencia del hepatocarcinoma (ARF) es una técnica de reciente adquisición, cuya eficacia y factores predictivos no han sido suficientemente evaluados. El presente estudio fue diseñado para este análisis. Pacientes y métodos: se han tratado 93 pacientes con hepatocarcinoma sobre hígado cirrótico sin criterios de resección ni de trasplante hepático. El tratamiento se realizó mediante abordaje percutáneo, laparoscópico o mediante laparotomía con dos tipos de electrodos de radiofrecuencia, electrodo refrigerado y de perfusión respectivamente. Resultados: la supervivencia global a los 1, 2 y 3 años fue del 88, 81 y 76%, con una supervivencia-libre de enfermedad (SLE) de 66, 31 y 17% respectivamente. El análisis multivariante demostró tres variables predictivas independientes: tamaño tumoral (< 3 cm frente > 3 cm; SLE a 1,2 y 3 años de 74, 44 y 30%, frente a 55, 12 y 0%; HR= 2,02; IC 95% 1,10-3,70; p = 0,02), número de nódulos (uno frente a más de uno; SLE a 1,2 y 3 años de 70, 36 y 22, frente a 50, 17 y 0%; HR= 1,92 IC 95% 0,95-3,93; p = 0,07) y tipo de electrodo (refrigerado frente a perfusión; SLE 80, 43 y 26% a 1, 2 y 3 años frente a 49, 12 y 0%; HR = 2,06; IC 95% 1,12-3,79; p = 0,02). Conclusiones: a pesar de que la ARF proporciona una supervivencia global aceptable, la SLE es notablemente inferior. El tamaño del tumor, el número de nódulos y el tipo de electrodo de ARF fueron variables independientes asociadas a la SLE.

Introduction: liver segmental resection and liver transplantation are both treatments intended for healing liver cancer. An adequate selection of patients eligible for transplantation is crucial, since organs available for transplants are usually scarce. For this reason, awareness of the prognostic factors of relapse is of great importance. We present a comprehensive review of our series in order to better understand these prognostic factors. Material and methods: we revised the cases of patients with hepatocellular carcinoma who underwent liver transplantation during the period 1994-2000, and present a detailed analysis of a series of variables which may be probably implicated in the appear-ance of relapse and which have an effect on survival. Results: after a mean follow-up of 33 months, the mortality rate was 27.5% and relapse occurred in 18.75% of cases. No history of alcohol abuse, the number and size of the nodules, the presence of macro and microscopic vascular invasion, and pTNM stage T4 were all factors associated with a significantly increased risk of relapse (pIntroducción: tanto la resección hepática segmentaria como el trasplante hepático son tratamientos con intención curativa para el hepatocarcinoma. La adecuada selección de los pacientes para el trasplante es de vital importancia dada la escasa disponibilidad de órganos. Por ello resulta fundamental el conocer los factores predictivos de recidiva tumoral, motivo por el que hacemos una exhaustiva revisión de nuestra serie. Material y métodos: revisamos los pacientes con hepatocarcinoma trasplantados en el periodo 1994-2000, y analizamos detalladamente una serie de variables con probable implicación en la recidiva tumoral y repercusión sobre la supervivencia. Resultados: tras un seguimiento medio de 33 meses, la mortalidad fue del 27,5% y la tasa de recidiva del 18,75%. La ausencia de alcoholismo, el número y el tamaño de nódulos, la invasión vascular macro y microscópica, y un estadio T4 en el clásico pTNM, se asociaban con un riesgo significativamente mayor de recidiva (p

New 1-[1-(1H-indol-3-yl) alkyl]-1H-indoles, surprisingly, have been obtained from the addition of indole to a variety of aldehydes under neat conditions. CaO, present in excess, was fundamental for carrying out the reaction with paraformaldehyde. Under the same reaction conditions, aromatic and heteroaromatic aldehydes afforded only classical bis (indolyl) aryl indoles. In this paper, the role of CaO, together with the regiochemistry and the mechanism of the reaction, are discussed in detail. The effect of some selected 3,3′- and 1,3′-diindolyl methane derivatives on cell proliferation of the hepatoma cell line FaO was also evaluated.

[Display omitted] • Low energy protons increase over-production of mitochondrial ROS in HepG2. • HepG2 DNA damages induces G 2 /M cell cycle arrest followed by apoptosis. • Proton radiation alters the plasma membrane ultrastructure of HepG2 cells. The increased use of proton therapy has led to the need of better understanding the cellular mechanisms involved. The aim of this study was to investigate the effects induced by the accelerated proton beam in hepatocarcinoma cells. An existing facility in IFIN-HH, a 3 MV Tandetron™ accelerator, was used to irradiate HepG2 human hepatocarcinoma cells with doses between 0 and 3 Gy. Colony formation was used to assess the influence of radiation on cell long-term replication. Also, the changes induced at the mitochondrial level were shown by increased ROS and ATP levels as well as a decrease in the mitochondrial membrane potential. An increased dose has induced DNA damages and G 2 /M cell cycle arrest which leads to caspase 3/7 mediated apoptosis and senescence induction. Finally, the morphological and ultrastructural changes were observed at the membrane level and the nucleus of the irradiated cells. Thus, proton irradiation induces both morphological and functional changes in HepG2 cells. [ABSTRACT FROM AUTHOR]

• Intracellular IGFBP1 attenuated hepatotoxicity induced by 24-epibrassinolide. • The accumulation of secreted IGFBP1 inhibited the phosphorylation of Akt. • IGFBP1 induced by 24-epbrassinolide was partially transcribed by ATF4. • The upregulation of IGFBP1 could be suppressed by ISRB and SCH772984. 24-epibrassinolide (EBR) is a ubiquitous steroidal phytohormone with anticancer activity. Yet the cytotoxic effects and mechanism of EBR on hepatocarcinoma (HCC) cells remain elusive. Cell counting kit-8 (CCK-8) assay was performed to evaluate cell viability. Real-time cell analysis (RTCA) technology and colony formation assays were used to evaluate cell proliferation. The apoptosis ratio was measured by flow cytometry. Seahorse XFe96 was applied to detect the effects of EBR on cellular bioenergetics. RNA-seq analysis was performed to investigate differences in gene expression profiles. Western blot and qRT-PCR were used to detect the changes in target molecules. EBR induced apoptosis and caused energy restriction in HCC, both of which were related to insulin-like growth factor-binding protein 1 (IGFBP1). EBR rapidly and massively induced IGBFP1, part of which was transcribed by activating transcription factor-4 (ATF4). The accumulation of secreted and cellular IGFBP1 had different important roles, in which secreted IGFBP1 affected cell energy metabolism by inhibiting the phosphorylation of Akt, while intracellular IGFBP1 acted as a pro-survival factor to resist apoptosis. Interestingly, the extracellular signal-regulated kinase (ERK) inhibitor SCH772984 and MAP/ERK kinase (MEK) inhibitor PD98059 not only attenuated the EBR-induced IGFBP1 expression but also the basal expression of IGFBP1. Thus, the treatment of cells with these inhibitors further enhances the cytotoxicity of EBR. Taken together, these findings suggested that EBR can be considered as a potential therapeutic compound for HCC due to its pro-apoptosis, restriction of energy metabolism, and other anti-cancer properties. Meanwhile, the high expression of IGFBP1 induced by EBR in HCC contributes to our understanding of the role of IGFBP1 in drug resistance. As a natural plant hormone, 24-epibrassinolide (EBR) resulted in HCC cells apoptosis and blocked energy metabolism. Meanwhile, HCC cells responded to the cytotoxicity of EBR by inducing apoptosis-related proteins (red font) and pro-survival proteins (green font) through transcription factors such as ATF4 and FOXO1, among which IGFBP1 acted as a pro-survival factor to inhibit mitochondrial-mediated apoptosis, but its extracellular aggregation suppressed the PI3K/Akt signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Racional - O hepatocarcinoma é uma das doenças malignas mais comuns em todo o mundo. O transplante hepático é boa opção terapêutica para os pacientes com hepatocarcinoma em fase inicial, alcançando índices de sobrevida semelhantes aos encontrados nos pacientes cirróticos transplantados sem malignidade hepática. Objetivo - Avaliar a evolução de pacientes cirróticos com hepatocarcinoma submetidos a transplante hepático no Serviço de Transplante Hepático do Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, PR. Métodos - Estudo retrospectivo dos pacientes cirróticos com hepatocarcinoma submetidos a transplante ortotópico de fígado no período de setembro de 1991 a setembro de 2000. O diagnóstico do tumor foi estabelecido durante os exames pré-transplante em cinco doentes e foi achado incidental no fígado nativo em três. Nos pacientes com diagnóstico pré-operatório de hepatocarcinoma adotou-se como critério de elegibilidade para o transplante, a presença de tumor único de diâmetro £ 5 cm ou até três lesões com diâmetro £ 3 cm cada, ausência de invasão tumoral da veia porta ou de metástases extra-hepática. Foram avaliados como parâmetros principais a sobrevida do paciente e a ocorrência de recidiva tumoral após o transplante. Resultados - A principal causa de doença hepática pré-transplante foi a hepatite por vírus C (50%). No exame do fígado explantado, a maioria dos pacientes (6/8, 75%) tinha lesão única; um paciente tinha dois nódulos e em outro detectou-se hepatocarcinoma multifocal incidentalmente no fígado nativo. O tamanho do tumor variou de 0,2 a 5,0 cm. Nenhum dos casos apresentou invasão vascular ou linfonodal. Todos os pacientes permaneceram vivos e livres de recurrência tumoral durante o tempo do estudo, sendo a mediana de seguimento de 18,5 meses (variando de 5-29 meses). Conclusão - O transplante hepático é boa opção terapêutica nos pacientes cirróticos com hepatocarcinoma em fase inicial. Com seleção adequada, o transplante hepático oferece excelentes índices de sobrevida livre de recurrência tumoral.