ß-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes.

Fibroblast growth factor 21 (FGF21) is secreted by hepatocytes as a peptide hormone to regulate glucose and lipid metabolism. FGF21 promotes hepatic ketogenesis and increases ketone body utilization in starvation. Histones are the target molecules of nutrients in regulating hepatic metabolic homeostasis. However, the effect of ketone bodies on FGF21 expression and the involvement of histones in it is not clear yet. The present study observed the effects of ß-hydroxybutyrate (ß-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells in vitro and in mice in vivo, and the role of histone deacetylases (HDACs) in ß-OHB-regulated FGF21 expression was investigated. The results showed that ß-OHB significantly upregulated FGF21 gene expression and increased FGF21 protein levels while it inhibited HDACs' activity in HepG2 cells. HDACs' inhibition by entinostat upregulated FGF21 expression and eliminated ß-OHB-stimulated FGF21 expression in HepG2 cells. Intraperitoneal injections of ß-OHB in mice resulted in the elevation of serum ß-OHB and the inhibition of hepatic HDACs' activity. Meanwhile, hepatic FGF21 expression and serum FGF21 levels were significantly increased in ß-OHB-treated mice compared with the control. It is suggested that ß-OHB upregulates FGF21 expression through inhibition of HDACs' activity in hepatocytes.

A Potential Mechanism of Temozolomide Resistance in Glioma-Ferroptosis.

Temozolomide (TMZ) is the first-line chemotherapy drug that has been used to treat glioma for over a decade, but the benefits are limited by half of the treated patients who acquired resistance. Studies have shown that glioma TMZ resistance is a complex process with multiple factors, which has not been fully elucidated. Ferroptosis, which is a new type of cell death discovered in recent years, has been reported to play an important role in tumor drug resistance. The present study reviews the relationship between ferroptosis and glioma TMZ resistance, and highlights the role of ferroptosis in glioma TMZ resistance. Finally, the investigators discussed the future orientation for ferroptosis in glioma TMZ resistance, in order to promote the clinical use of ferroptosis induction in glioma treatment.

Ibuprofen induces ferroptosis of glioblastoma cells via downregulation of nuclear factor erythroid 2-related factor 2 signaling pathway.

Ferroptosis is a newly discovered type of cell death decided by iron-dependent lipid peroxidation, but its role in glioblastoma cell death remains unclear. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has been associated with antitumorigenic effects in many cancers. In this study, we first found that ibuprofen inhibited the viabilities of glioblastoma cells in vitro and in vivo, accompanied by abnormal increase in intracellular lipid peroxidation. Further study showed that the cell growth inhibition caused by ibuprofen could be rescued by the ferroptosis inhibitors deferoxamine (DFO), ferrostatin-1 and Liproxstatin-1. Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) are key regulators of ferroptosis. Our data showed that Nrf2, GPX4 and SLC7A11 were downregulated in glioblastoma cells under ibuprofen treatment. Interestingly, we found that decreased mRNA expression of GPX4 and SLC7A11 was accompanied with reduced Nrf2, which is a redox sensitive transcription factor that controls the expression of intracellular redox-balancing proteins such as GPX4 and SLC7A11. All the data suggested that Nrf2 could regulate the expression of GPX4 and SLC7A11 in glioma cells. Taken together, our findings reveal that ibuprofen could induce ferroptosis of glioblastoma cells via downregulation of Nrf2 signaling pathway and is a potential drug for glioma treatment.

Grifolic acid induces GH3 adenoma cell death by inhibiting ATP production through a GPR120-independent mechanism.

BACKGROUND: Grifolic acid is a derivative of grifolin, an antitumor natural compound, and it was reported as an agonist of free fatty acid receptor GPR120. Little is known about its antitumor effects and the involvement of GPR120. METHODS: GH3 cells, the rat anterior pituitary adenoma cells, were cultured and the cell death was measured by MTT assay and Annexin V/PI staining. The mitochondrial membrane potential (MMP) of GH3 cells was measured by JC-1 staining. Cellular ATP levels and the intracellular NAD/NADH ratio were measured. GPR120 expression in GH3 cells was observed by RT-PCR and Western Blot, and siRNA was used to inhibit GPR120 expression in GH3 cells. RESULTS: Grifolic acid dose- and time-dependently induced the necrosis of GH3 cells. Grifolic acid significantly reduced the mitochondrial membrane potential (MMP) and decreased cellular ATP levels in GH3 cells. In contrast, the MMP of isolated mitochondria was not decreased by grifolic acid. The intracellular NAD/NADH ratio was significantly increased by grifolic acid. GPR120 is expressed in GH3 cells, but GPR120 agonists such as EPA, GW9508 and TUG891 did not affect the viability of GH3 cells. Moreover, GPR120 siRNA knockdown showed no significant influence on grifolic acid-induced GH3 cell death. CONCLUSION: Grifolic acid induces GH3 cell death by decreasing MMP and inhibiting ATP production, which may be due to the inhibition of NADH production through a GPR120-independent mechanism.

Grifolic acid induces mitochondrial membrane potential loss and cell death of RAW264.7 macrophages.

Grifolic acid is a phenolic compound that was first extracted from the mushroom Albatrellus confluens; it acts as an agonist of the free fatty acid receptor (FFAR4). FFAR4 is expressed in macrophages and mediates the anti­inflammatory effects of n­3 unsaturated free fatty acids. In the present study, the effects of grifolic acid on macrophages were observed in mouse RAW264.7 cells. It was demonstrated that grifolic acid (2.5­20 µmol/l) treatment reduced RAW264.7 cell viability in a dose­ and time­dependent manner. The number of apoptotic cells significantly increased following grifolic acid treatment compared with the untreated control cells. Grifolic acid treatment resulted in a significant decrease in cellular adenosine 5'­triphosphate (ATP) content in RAW264.7 cells. Mitochondrial membrane potential (MMP), as measured by JC­1 staining, was significantly diminished by grifolic acid treatment in a dose­ and time­dependent manner. Treatment with cyclosporine A, a protector of MMP, attenuated grifolic acid­induced reduction of MMP and viability in RAW264.7 cells. FFAR4 knockdown did not significantly influence grifolic acid­induced reduction of cell viability, ATP levels or MMP. In conclusion, grifolic acid may induce macrophage cell death by reducing MMP and by inhibiting ATP production probably in an FFAR4­independent manner.

The PHLDB1 rs498872 (11q23.3) polymorphism and glioma risk: A meta-analysis.

The association between the rs498872 single nucleotide polymorphism (SNP) and glioma risk has been studied, but these studies have yielded conflicting results. In order to explore this association, we performed a meta-analysis. A comprehensive literature search was performed using PubMed and EMBASE database, with the last search up to August 23, 2013. Six articles including 10 case-control studies in English with 18 002 controls and 8434 cases were eligible for the meta-analysis. Subgroup analyses were conducted by source of controls and ethnicity. The combined results showed that rs498872 polymorphism was significantly associated with glioma risks (TT vs CC: OR = 1.337, 95% CI = 1.222-1.462; TC vs CC: OR = 1.173, 95% CI = 1.081-1.272; dominant model: OR = 1.199, 95% CI = 1.101-1.306; recessive model: OR = 1.237, 95% CI = 1.135-1.347; additive model: OR = 1.156, 95% CI = 1.085-1.232). Moreover, there was increased cancer risk in all genetic models after stratification of the SNP data by the source of controls and ethnicity, and no evidence of publication bias was produced. Our meta-analysis suggested that rs498872 polymorphism was associated with increased risk of glioma. However, additional studies exploring the combined effects of rs498872 polymorphisms in Asian population should be investigated.

Berberine sensitizes rapamycin­mediated human hepatoma cell death in vitro.

Rapamycin is clinically used as an immunosuppressant. Increasing evidence suggests that rapamycin has an important inhibitory role in the development and progression of different types of cancer and that it is a promising candidate for cancer chemotherapy. Berberine is an isoquinoline alkaloid isolated from medicinal plant species, which has been used in traditional Chinese medicine with no significant side effects. Recent research has demonstrated that berberine has anticancer activity against various types of cancer, mediated through the suppression of mammalian target of rapamycin (mTOR). The present study aimed to investigate the in vitro synergistic anticancer effect of combined treatment of rapamycin at various concentrations (0, 10, 50, 100 and 200 nM) and berberine (62.5 µM) in SMMC7721 and HepG2 hepatocellular carcinoma (HCC) cell lines, and the potential underlying molecular mechanism. The combined use of rapamycin and berberine was found to have a synergistic cytotoxic effect, with berberine observed to maintain the cyotoxic effect of rapamycin on HCC cells at a lower rapamycin concentration. Moreover, the cells treated with the combination of the two agents exhibited significantly decreased protein levels of phosphorylated (p)­p70S6 kinase 1 (Thr389), the downstream effector of mTOR, compared with the cells treated with rapamycin or berberine alone. Furthermore, overexpression of cluster of differentiation (CD) 147, a transmembrance glycoprotein associated with the anticancer effects of berberine, was found to upregulate p­mTOR expression and inhibit cell death in SMMC7721 cells co­treated with rapamycin and berberine. In conclusion, the findings of the present study suggest that the combined use of rapamycin and berberine may improve HCC therapy through synergistically inhibiting the mTOR signaling pathway, which is at least in part, mediated through CD147.