• Biomarkers
• Diagnostic performance
• HCC
• HCV
• Toll-like receptor 4
• miRNA-15b-5p

• Akt
• Lipid metabolism
• PI3K pathway
• Signal transduction
• Sphingolipids

• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/enzymology
• Neoplasms/genetics
• Lipid Metabolism
• Signal Transduction
• Phosphatidylinositol 3-Kinases/metabolism
• Phosphatidylinositol 3-Kinases/genetics
• Animals

• Ceramides
• Hepatocellular carcinoma
• Isotope tracing
• Lipid metabolism
• Phospholipids
• Zebrafish

• beta Catenin/metabolism
• beta Catenin/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Zebrafish/metabolism
• Zebrafish/genetics
• Humans
• Animals
• Phosphatidylcholines/metabolism
• Liver Neoplasms/metabolism
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Lipid Metabolism/genetics
• Animals, Genetically Modified
• Phospholipids/metabolism
• Cell Line, Tumor
• Lipidomics/methods

• R00 CA215307 NCI NIH HHS
• R01 DK115824 NIDDK NIH HHS
• R21 DK073181 NIDDK NIH HHS
• R01 CA222570 NCI NIH HHS
• R01 DK122001 NIDDK NIH HHS

• Humans
• Sorafenib/pharmacology
• Sorafenib/therapeutic use
• Proto-Oncogene Proteins c-akt/metabolism
• Hep G2 Cells
• Calotropis/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Reactive Oxygen Species/metabolism
• Plant Bark/metabolism
• TOR Serine-Threonine Kinases/metabolism
• Phosphatidylinositol 3-Kinase/metabolism
• Apoptosis
• Cell Line, Tumor
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Acetates

• National Science Research and Innovation Fund (NSRF) of Thailand
• Faculty of Medical Science, Naresuan University
• Agricultural Research Development Agency (Public Organization)
• Center of Excellence for Innovation in Chemistry (PERCH-CIC)
• Global and Frontier Research University Fund, Naresuan University

• Ceramides
• Flux analysis
• Isotope tracing
• Lipid metabolism

• R00 CA215307 NCI NIH HHS
• R01 CA222570 NCI NIH HHS

• CSNK1A1
• EGFR
• EPS15
• HCC
• ITGB5
• Sorafenib

• Humans
• Carcinoma, Hepatocellular/metabolism
• Sorafenib/pharmacology
• Sorafenib/therapeutic use
• Liver Neoplasms/metabolism
• Up-Regulation
• Proto-Oncogene Proteins c-akt/metabolism
• Cell Proliferation
• TOR Serine-Threonine Kinases/metabolism
• ErbB Receptors
• Drug Resistance, Neoplasm
• Cell Line, Tumor
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use

• CER
• CRLM
• Liver Regeneration
• SMPD3

• Mice
• Animals
• Matrix Metalloproteinase 2
• Liver Regeneration
• Sphingomyelin Phosphodiesterase
• Ceramides
• Exosomes
• Colorectal Neoplasms/genetics
• Liver Neoplasms/metabolism

• Biomarker
• Cancer therapy
• Hepatocellular carcinoma
• PI3K/Akt
• PTEN

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide with high prevalence and lethality. Due to insidious onset and lack of early symptoms, most HCC patients are diagnosed at advanced stages without adequate methods but systemic therapies. PI3K/AKT/mTOR signaling pathway plays a crucial role in the progression and development of HCC. Aberrant activation of PI3K/AKT/mTOR pathway is involved in diverse biological processes, including cell proliferation, apoptosis, migration, invasion and angiogenesis. Therefore, the development of PI3K-targeted inhibitors is of great significance for the treatment of HCC. DHW-208 is a novel 4-aminoquinazoline derivative pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in HCC and investigate its underlying mechanism. DHW-208 could inhibit the proliferation, migration, invasion and angiogenesis of HCC through the PI3K/AKT/mTOR signaling pathway in vitro. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in HCC. Therefore, DHW-208 is a candidate compound to be developed as a small molecule PI3K inhibitor for the treatment of HCC, and our study provides a certain theoretical basis for the treatment of HCC and the development of PI3K inhibitors.

Chemotherapy is the major treatment modality for advanced or unresectable hepatocellular carcinoma (HCC). Unfortunately, chemoresistance carries a poor prognosis in HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects; however, recent reports showed ceramide resistance, which limits the development of the ceramide-based cancer treatment diTFPP, a novel phenoxyphenol compound that has been shown to sensitize HCC cells to ceramide treatment. Here, we further clarified the mechanism underlying diTFPP-mediated sensitization of HCC to C₂-ceramide-induced stresses, including oxidative stress, ER stress, and autophagic stress, especially the modulation of LAMP2 glycosylation, the lysosomal membrane protein that is crucial for autophagic fusion. This study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics.

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the leading cause of cancer-related mortality worldwide. Chemotherapy is the major treatment modality for advanced or unresectable HCC; unfortunately, chemoresistance results in a poor prognosis for HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects. However, recent reports suggest that sphingolipid metabolism in ceramide-resistant cancer cells favors the conversion of exogenous ceramides to prosurvival sphingolipids, conferring ceramide resistance to cancer cells. However, the mechanism underlying ceramide resistance remains unclear. We previously demonstrated that diTFPP, a novel phenoxyphenol compound, enhances the anti-HCC effect of C₂-ceramide. Here, we further clarified that treatment with C₂-ceramide alone increases the protein level of CERS2, which modulates sphingolipid metabolism to favor the conversion of C₂-ceramide to prosurvival sphingolipids in HCC cells, thus activating the unfolded protein response (UPR), which further initiates autophagy and the reversible senescence-like phenotype (SLP), ultimately contributing to C₂-ceramide resistance in these cells. However, cotreatment with diTFPP and ceramide downregulated the protein level of CERS2 and increased oxidative and endoplasmic reticulum (ER) stress. Furthermore, insufficient LAMP2 glycosylation induced by diTFPP/ceramide cotreatment may cause the failure of autophagosome–lysosome fusion, eventually lowering the threshold for triggering cell death in response to C₂-ceramide. Our study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics.

The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin (PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills (XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma (HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHP-associated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.

To confirm the effect of XHP on HCC and the possible mechanisms involved.

The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Cell-based experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP (0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay. Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction (RT-qPCR), respectively. Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway. Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.

The following 12 compounds were identified in XHP using high-resolution mass spectrometry: Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625 mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose- and time-dependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract (0.625 mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins (e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.

XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3. Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.

• Hepatocellular carcinoma
• Xihuang pills
• Apoptosis
• Antitumour
• Phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin pathway

• Combination therapy
• Epithelial–mesenchymal transition
• Hepatocellular carcinoma
• Tumour microenvironment
• Tyrosine kinase inhibitors

• Chemoimunotherapy
• Hepatocellular carcinoma
• Natural killer cells
• Sorafenib

8-gingerol (8-Gin) is the series of phenolic substance that is extracted from ginger. Although many studies have revealed that 8-Gin has multiple pharmacological properties, the possible underlying mechanisms of 8-Gin against myocardial fibrosis (MF) remains unclear. The study examined the exact role and potential mechanisms of 8-Gin against isoproterenol (ISO)-induced MF. Male mice were intraperitoneally injected with 8-Gin (10 and 20 mg/kg/d) and concurrently subcutaneously injected with ISO (10 mg/kg/d) for 2 weeks. Electrocardiography, pathological heart morphology, myocardial enzymes, reactive oxygen species (ROS) generation, degree of apoptosis, and autophagy pathway-related proteins were measured. Our study observed 8-Gin significantly reduced J-point elevation and heart rate. Besides, 8-Gin caused a marked decrease in cardiac weight index and left ventricle weight index, serum levels of creatine kinase and lactate dehydrogenase (CK and LDH, respectively), ROS generation, and attenuated ISO-induced pathological heart damage. Moreover, treatment with 8-Gin resulted in a marked decrease in the levels of collagen types I and III and TGF-β in the heart tissue. Our results showed 8-Gin exposure significantly suppressed ISO-induced autophagosome formation. 8-Gin also could lead to down-regulation of the activities of matrix metalloproteinases-9 (MMP-9), Caspase-9, and Bax protein, up-regulation of the activity of Bcl-2 protein, and alleviation of cardiomyocyte apoptosis. Furthermore, 8-Gin produced an obvious increase in the expressions of the PI3K/Akt/mTOR signaling pathway-related proteins. Our data showed that 8-Gin exerted cardioprotective effects on ISO-induced MF, which possibly occurred in connection with inhibition of ROS generation, apoptosis, and autophagy via modulation of the PI3K/Akt/mTOR signaling pathway.

• 8-gingerol
• PI3K/Akt/mTOR signaling pathway
• apoptosis
• autophagy
• myocardial fibrosis
• reactive oxygen species

Liver cancer remains one of the leading causes of cancer deaths worldwide. The therapeutic effect of oxaliplatin on liver cancer is often limited by acquired resistance of the cancer cells. Abnormal activation of the PI3K/AKT pathway plays an important role in the acquired resistance of oxaliplatin. The present study investigated the effects of the PI3K inhibitor LY-294002 and AKT inhibitor MK2206 on the chemosensitivity of oxaliplatin-resistant liver cancer cells and the molecular mechanism involved. An oxaliplatin-resistant liver cancer cell line HepG2^R was developed. MTT assay, clone formation experiments, flow cytometry and Annexin V-FITC/PI staining were used to determine the proliferation, cycle and apoptosis of HepG2^R cells when oxaliplatin was combined with LY-294002 or MK2206 treatment. The effects of LY-294002 and MK-2206 on the abnormal activation of PI3K/AKT pathway and hypoxia inducible factor (HIF)-1α protein level in HepG2^R cells were detected using western blotting. The results indicated that the PI3K/AKT pathway is stably activated in HepG2^R cells. Compared with the AKT inhibitor MK2206, the PI3K inhibitor LY-294002 more effectively downregulated the phosphorylation levels of p85, p110α, p110β, p110γ and AKT in the PI3K/AKT pathway in HepG2^R cells, and more effectively inhibited the proliferation of the cells. LY-294002 enhanced the chemotherapy sensitivity of HepG2^R cells to oxaliplatin by inducing G₀/G₁ phase arrest and increasing the proportion of apoptotic cells. In addition, LY-294002 reduced the level of HIF-1α, which is highly expressed in HepG2^R cells. It was concluded that LY-294002 enhanced the chemosensitivity of liver cancer cells to oxaliplatin by inhibiting the PI3K/AKT signaling pathway, which may be related to the inhibition of HIF-1α expression. These findings may have clinical significance for the treatment of oxaliplatin-resistant liver cancer.

• LY‑294002
• MK‑2206
• PI3K/AKT
• hepatocellular carcinoma
• hypoxia inducible factor‑1α
• oxaliplatin

Lupeol liposomes, modified with Gal-PEG-DSPE, were developed following a thin-film dispersion method. Then, the morphology, physicochemical properties, and in vitro release properties of those liposomes were investigated. The scanning electron microscopic images showed that most of the liposomes were spherical particles; they were similar in size and uniformly dispersed. Both lupeol liposomes and Gal-lupeol liposomes exhibited an average particle size of about 100 nm. The encapsulation efficiency was greater than 85%. The encapsulation efficiency of lupeol liposome and Gal-lupeol liposome, stored with 15% sucrose as glycoprotein for 6 months, was higher than 80%; although the particle size increased, they remained within 200 nm. The cell-uptake study demonstrated that the Gal-lupeol-liposome uptake efficiency was the highest in HepG2 cells. The HepG2 cells treated with the Gal-lupeol liposomes had higher apoptotic efficiency than the lupeol liposome and free lupeol. After HepG2 cells were treated with Gal-lupeol liposome, the expressions of AKT/mTOR-related proteins (p-AKT308 and p-AKT473) were also significantly reduced than the lupeol-liposome and free lupeol group. The in vivo targeting studies showed that Gal-NR-L exhibited liver-targeting effects on FVB mice. The pharmacodynamic study was performed by transfecting AKT and c-MET via the high-pressure tail vein of FVB mice. After Gal-lupeol-L administration, the liver index and liver weight of mice were less than those non-targeted group. The histopathological study showed that the lobular structure in the mice liver was clearer, the vacuoles were more obvious, and the cytoplasm was more abundant after Gal-lupeol-L administration. Also, the qRT-PCR study showed that AFP, GPC3, and EpCAM mRNA expression levels were significantly lower than those non-targeted lupeol-liposomes.

• Gal-lupeol liposomes
• Nile Red
• encapsulation efficiency
• high-pressure tail vein
• liver targeted

Sonodynamic therapy (SDT) is considered a promising therapeutic strategy for the effective elimination of cancer cells. However, developing novel sonosensitizers with potentially high SDT efficacy remains a considerable challenge. Herein, we utilized near-infrared dye IR820 nanobubbles (NBs) combined with a dual PI3K/mTOR inhibitor PI-103 for the SDT treatment of hepatocellular carcinoma (HCC) in vitro.

The generated reactive oxygen species (ROS) were quantified using 2,7-dichlorodihydrofluorescein diacetate to determine the feasibility of using IR820 NBs as a potential sonosensitizer. The inhibition effects of the synergistic therapy was examined using the cell counting Kit 8 assay and apoptosis assay. JC-1 staining was performed to study mitochondrial membrane depolarization, and the transwell assay was used for cell migration analysis.

The particle size and zeta potential of IR820 NBs were 545.5±93.1 nm and −5.19±1.73 mV, respectively. ROS accumulation was observed after HepG2 cells were treated with IR820 NBs under ultrasound irradiation. The SDT combined with PI-103 group inhibited cell viability and migration more strongly than the other groups (P < 0.01). The apoptosis assay also demonstrated a relatively high anti-HCC efficacy with the synergistic therapy, while JC-1 staining showed a decrease in the mitochondrial membrane potential after the combined treatment.

The combination of SDT and PI-103 was very effective in suppressing HCC proliferation, which might help develop new minimally invasive cancer treatment strategies.

• IR820 nanobubbles
• PI3K/mTOR inhibitor
• minimally invasive cancer treatment strategy
• sonosensitizer

A viral infection that involves virus invasion, protein synthesis, and virion assembly is typically accompanied by sharp fluctuations in the intracellular levels of metabolites. Under certain conditions, dramatic metabolic shifts can result in various types of cell death. Here, we review different types of adenovirus-induced cell death associated with changes in metabolic profiles of the infected cells. As evidenced by experimental data, in most cases changes in the metabolome precede cell death rather than represent its consequence. In our previous study, the induction of autophagic cell death was observed following adenovirus-mediated lactate production, acetyl-CoA accumulation, and ATP release, while apoptosis was demonstrated to be modulated by alterations in acetate and asparagine metabolism. On the other hand, adenovirus-induced ROS production and ATP depletion were demonstrated to play a significant role in the process of necrotic cell death. Interestingly, the accumulation of ceramide compounds was found to contribute to the induction of all the three types of cell death mentioned above. Eventually, the characterization of metabolite analysis could help in uncovering the molecular mechanism of adenovirus-mediated cell death induction and contribute to the development of efficacious oncolytic adenoviral vectors.

• autophagy
• metabolites
• viruses

• Adenoviridae/genetics
• Adenoviridae/physiology
• Apoptosis/genetics
• Apoptosis/physiology
• Cell Death/genetics
• Cell Death/physiology
• Genetic Vectors/genetics
• Genetic Vectors/physiology
• Humans
• Metabolome/genetics
• Metabolome/physiology

Sphingomylin participates in sperm function in animals, and also regulates the Akt and ERK signaling pathways, both of which are associated with the asthenospermia. Sphingomyelin synthase 2 (SMS2) is involved in the biosynthesis of sphingomylin. To determine the relationship between SMS2 and human sperm function, we analyzed the distribution of SMS2 in human sperm and testes, and SMS2 expression in patients with asthenospermia and normozoospermia; human sperm were treated with anti-SMS2, and the sperm motility, penetration ability into methylcellulose, capacitation and acrosome reaction, and sperm [Ca²⁺]i imaging were evaluated, while the Akt and ERK pathway and cleaved caspase 3 were also analyzed. Results showed that SMS2 was localized in the testis and human sperm, and the protein levels of normozoospermia were higher than asthenospermia. Inhibition of SMS2 activity significantly decreased sperm motility and penetration ability into methylcellulose, but had no influence on capacitation and acrosome reaction, or on intracellular [Ca²⁺]i compared to IgG-treated control groups. Moreover, the phosphorylation level of Akt was decreased, whereas the phosphorylation of ERK and cleaved-caspase 3 levels were significantly increased. Taken together, SMS2 can affect sperm motility and penetration ability into methylcellulose, and participate in apoptosis associated with the Akt and ERK signaling pathways.

• Akt
• ERK
• SMS2
• sperm motility

Excision Repair Cross-Complementation group 6-like (ERCC6L) has been shown to exhibit carcinogenic effect in several malignant tumors. However, the function and molecular mechanism of the ERCC6L in hepatocellular carcinoma (HCC) have not been investigated extensively.

Immunohistochemistry analyses were used to detect ERCC6L expression in a HCC tissue microarray, and the Chi-square test was used to assess the correlation between ERCC6L expression and patients’ clinicopathological features. shRNA was used to down-regulation ERCC6L expression in HCC cell lines. MTT assay, plate clone formation assay, flow cytometry, caspase 3/7 activity and migration assays were performed to evaluate the impact of ERCC6L on HCC cells in vitro. Nude mice xenograft models were used to assess the role of ERCC6L in vivo. The regulatory of mechanism of PI3K/AKT pathway was evaluated by western blotting.

ERCC6L was highly expressed in HCC tissue compared with tumor adjacent tissues in 90 paired samples. ERCC6L expression positively correlated with gender, tumor encapsulation, and pathological stage. Patients with low ERCC6L expression had significantly longer OS than those with high ERCC6L expression. Knockdown of ERCC6L expression significantly inhibited proliferation, invasion and metastasis in vitro and tumor growth in vivo, and it promoted cell cycle arrest and apoptosis. Mechanistic analyses revealed that PI3K/AKT and NF-κB signaling pathway were inhibited by silencing ERCC6L.

These results demonstrate that ERCC6L plays a critical role in HCC progression, and thereby might be a potential therapeutic target for HCC patients.

• AKT
• ERCC6L
• Hepatocellular carcinoma
• Oncogene
• PI3K

• EMT
• NSCLC
• gemcitabine
• sorafenib
• synergistic effect

• High-fat high-fructose
• Insulin resistance
• Renal lipotoxicity
• Statins
• Vildagliptin

• anaplastic thyroid carcinoma
• ceramide
• glucosylceramide
• migration
• motility

Hepatocellular carcinoma (HCC) is one of the most severe diseases worldwide. For the different stages of HCC, there are different clinical treatment strategies, such as surgical therapy for the early stage, and transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) for intermediate-stage disease. Systemic treatment, which uses mainly targeted drugs, is the standard therapy against advanced HCC. Sorafenib is an important first-line therapy for advanced HCC. As a classically effective drug, sorafenib can increase overall survival markedly. However, it still has room for improvement because of the heterogeneity of HCC and acquired resistance. Scientists have reported the acquired sorafenib resistance is associated with the anomalous expression of certain genes, most of which are also related with HCC onset and development. Combining sorafenib with inhibitors targeting these genes may be an effective treatment. Combined treatment may not only overcome drug resistance, but also inhibit the expression of carcinoma-related genes. This review focuses on the current status of sorafenib in advanced HCC, summarizes the inhibitors that can combine with sorafenib in the treatment against HCC, and provides the rationale for clinical trials of sorafenib in combination with other inhibitors in HCC. The era of sorafenib in the treatment of HCC is far from over, as long as we find better methods of medication.

• combination
• hepatocellular carcinoma
• inhibitor
• resistance
• sorafenib

• Apoptosis
• CD13
• Cellular penetration
• NGR-sIL-24
• Targeted therapy

• A549 Cells
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Apoptosis/physiology
• Cell Line, Tumor
• Cell Transformation, Neoplastic/drug effects
• Cell-Penetrating Peptides/pharmacology
• Endoplasmic Reticulum Chaperone BiP
• Humans
• Oligopeptides/metabolism
• Recombinant Fusion Proteins/pharmacology
• Signal Transduction/drug effects
• U937 Cells

• Chlamydia trachomatis
• DJ-1 protein
• ERK1/2 pathway
• Pgp3 protein
• apoptosis

• Apoptosis
• BZG
• Hepatocellular carcinoma (HCC)
• Sorafenib
• p-AKT
• p-ERK

• tanshinone IIA
• imatinib
• acute T lymphocytic leukemia
• PI3K/AKT/mTOR signaling pathway

• Abietanes/administration & dosage
• Abietanes/pharmacology
• Animals
• Antineoplastic Agents, Phytogenic/administration & dosage
• Antineoplastic Agents, Phytogenic/pharmacology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Imatinib Mesylate/administration & dosage
• Imatinib Mesylate/pharmacology
• Mice
• Phosphatidylinositol 3-Kinases/metabolism
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism
• Xenograft Model Antitumor Assays

• CBA/CAJ mouse
• CDK1
• Cell Cycle
• HCC
• PLK1

• Animals
• Apoptosis/genetics
• CDC2 Protein Kinase/metabolism
• Cell Cycle/genetics
• Cell Cycle Proteins/metabolism
• Cell Line, Tumor
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic
• Gene Ontology
• Gene Regulatory Networks
• Liver Neoplasms, Experimental/genetics
• Liver Neoplasms, Experimental/metabolism
• Male
• Mice
• Mice, Inbred CBA
• Protein Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins/metabolism
• Signal Transduction
• Transcription, Genetic
• Transcriptome
• Polo-Like Kinase 1

Gold nanoparticles are the most promising candidate in cancer treatment due to their physiochemical properties and increased use in photothermal therapy (PTT). In the present study, spherical gold nanoparticles (AuNPs) were synthesized using citrate reduction method. The particles were then characterized using UV-VIS spectroscopy and transmission electron microscope. A hepatocellular carcinoma cell line (HepG2) was incubated with sorafenib and/or non-irradiated or laser-irradiated AuNPs for 48 hrs. The cytotoxic effect of different treatment modalities was determined using MTT assay. Furthermore, apoptosis was determined by flow cytometry using annexin V/propidium iodide, as well as estimating the level of caspases. Results showed that AuNPs and sorafenib reduced HepG2 cell viability, and the cytotoxicity was associated with increased release of LDH in the culture medium. The recorded cytotoxicity was attributed to enhanced apoptosis as revealed by increased cellular caspases (3, 8 and 9), that was further confirmed by flow cytometry. The most notable cytotoxic effect was recorded when combining sorafenib with laser-irradiated AuNPs. In conclusion, a synergistic cytotoxic effect was observed between sorafenib and laser-irradiated AuNPs against the growth of HepG2, suggesting the potential substitution of large toxic doses of sorafenib by lower doses in combination with photothermal therapy.

• Gold Nanoparticles
• Hepatocellular carcinoma
• photothermal therapy
• sorafenib

• PDK1/Akt/mTOR signaling
• apoptosis
• liver cancer cells
• ponatinib
• proliferation

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Cycle Checkpoints/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Drug Resistance, Neoplasm
• Humans
• Imidazoles/pharmacology
• Liver Neoplasms/metabolism
• Protein Kinase Inhibitors/pharmacology
• Protein Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Pyridazines/pharmacology
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism

• Wnt/β-catenin pathway
• epithelial-mesenchymal transition
• hepatocellular carcinoma
• long noncoding RNA cardiac hypertrophy-related factor
• microRNA-211
• phosphoinositide-3-kinase/protein kinase B pathway

miR-15b-5p has frequently been reported to function as a biomarker in some malignancies; however, the function of miR-15b-5p in hepatocellular carcinoma (HCC) and its molecular mechanism are still not well understood. The present study was designed to confirm the clinical value of miR-15b-5p and further explore its underlying molecular mechanism. A comprehensive investigation of the clinical value of miR-15b-5p in HCC was investigated by data mining The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets as well as literature. In addition, intersected target genes of miR-15b-5p were predicted using the miRWalk database and differentially expressed genes of HCC from TCGA. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out. Then, a protein-protein interaction network (PPI) was constructed to reveal the interactions between some hub target genes of miR-15b-5p. The miR-15b-5p expression level in HCC was predominantly overexpressed compared with non-HCC tissues samples (SMD=0.618, 95% CI: 0.207, 1.029; P<0.0001) based on 991 HCC and 456 adjacent non-HCC tissue samples. The pooled summary receiver operator characteristic (SROC) of miR-15b-5p was 0.81 (Q*=0.74), and the pooled sensitivity and specificity of miR-15b-5p in HCC were 72% (95% CI: 69–75%) and 68% (95% CI: 65–72%), respectively. Bioinformatically, 225 overlapping genes were selected as prospective target genes of miR-15b-5p in HCC, and profoundly enriched GO terms and KEGG pathway investigation in silico demonstrated that the target genes were associated with prostate cancer, proximal tubule bicarbonate reclamation, heart trabecula formation, extracellular space, and interleukin-1 receptor activity. Five genes (ACACB, RIPK4, MAP2K1, TLR4 and IGF1) were defined as hub genes from the PPI network. The high expression of miR-15b-5p could play an essential part in hepatocarcinogenesis through diverse regulation approaches.

• GEO
• TCGA
• hepatocellular carcinoma
• miR-15b-5p
• target genes

In this study, acetaminophen (APAP)-induced acute liver injury mice model was used to investigate the effects of C2-ceramide and oltipraz on hepatocyte nuclear factor 1 (HNF-1) and glutathione S-transferase A1 (GSTA1). Notably, C2-ceramide caused alteration in mice serum transaminases and liver tissue indexes, and aggravated hepatic injury, while oltipraz alleviated hepatic injury. By screening, the optimal concentrations of C2-ceramide and oltipraz were confirmed to be 120 and 150 μmol/L, respectively. In histopathology, karyolysis and more necrotic cells and bleeding spots were appeared on administration of C2-ceramide, but only a small amount of inflammatory cells infiltration was seen after oltipraz treatment. In addition, RT-PCR and western blot results revealed that the mRNA and protein expression levels of HNF-1 and GSTA1 in liver were significantly decreased (p < 0.01) with the administration of 120 μmol/L C2-ceramide. Meanwhile, GSTA1 content in serum increased up to 1.27-fold. In contrast, 150 μmol/L oltipraz incorporation to APAP model mice resulted in obvious elevation (p < 0.01) in the mRNA and protein expression levels of HNF-1 and GSTA1 in liver, and serum GSTA1 content decreased up to 0.77-fold. In conclusion, C2-ceramide could down-regulate the expression of HNF-1 and GSTA1 which exacerbated hepatic injury, while oltipraz could up-regulate the expression of HNF-1 and GSTA1 which mitigated hepatic injury.

• C2-ceramide
• GSTA1
• HNF-1
• acetaminophen
• liver injury
• oltipraz

• ceramide
• co-delivery
• hepatocellular carcinoma
• liposomes
• sorafenib

• CASC2
• Nf-κB
• hepatocellular carcinoma
• miR-362-5p
• oncogenesis

• Akt
• Apoptosis
• Hepatocellular carcinoma
• PTEN
• Rg3
• Sorafenib

• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Blotting, Western
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Survival/drug effects
• Drug Synergism
• Gene Expression Regulation, Neoplastic
• Ginsenosides/administration & dosage
• Ginsenosides/pharmacology
• Hep G2 Cells
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Niacinamide/administration & dosage
• Niacinamide/analogs & derivatives
• Niacinamide/pharmacology
• PTEN Phosphohydrolase/metabolism
• Phenylurea Compounds/administration & dosage
• Phenylurea Compounds/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Sorafenib

• Adverse reaction
• Itch
• Mast cell
• PI3K
• Sorafenib
• Stem cell factor

• Adult
• Aged
• Aged, 80 and over
• Androstadienes/pharmacology
• Antineoplastic Agents/adverse effects
• Apoptosis/drug effects
• Biopsy
• Cell Count
• Cell Degranulation/drug effects
• Cell Proliferation/drug effects
• Drug Eruptions/etiology
• Drug Eruptions/pathology
• Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Female
• Flavonoids/pharmacology
• Humans
• Male
• Mast Cells/drug effects
• Mast Cells/physiology
• Middle Aged
• Niacinamide/adverse effects
• Niacinamide/analogs & derivatives
• Organ Culture Techniques
• Phenylurea Compounds/adverse effects
• Phosphatidylinositol 3-Kinases/metabolism
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors/adverse effects
• Signal Transduction/drug effects
• Skin/cytology
• Skin/drug effects
• Skin/metabolism
• Skin/pathology
• Sorafenib
• Stem Cell Factor/antagonists & inhibitors
• Stem Cell Factor/metabolism
• Vascular Endothelial Growth Factor A
• Wortmannin
• Young Adult

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

• Hepatocellular carcinoma
• Systemic therapy
• Chemotherapy
• Molecular targeted therapy
• Cytotoxic therapy
• Immunotherapy
• Perspectives