An aryl hydrocarbon receptor induces VEGF expression through ATF4 under glucose deprivation in HepG2

BACKGROUND: Aryl hydrocarbon receptor (AhR) not only regulates drug-metabolizing enzyme expression but also regulates cancer malignancy. The steps to the development of malignancy include angiogenesis that is induced by tumor microenvironments, hypoxia, and nutrient deprivation. Vascular endothelial growth factor (VEGF) plays a central role in the angiogenesis of cancer cells, and it is induced by activating transcription factor 4 (ATF4). RESULTS: Recently, we identified that glucose deprivation induces AhR translocation into the nucleus and increases CYP1A1 and 1A2 expression in HepG2 cells. Here, we report that the AhR pathway induces VEGF expression in human hepatoblastoma HepG2 cells under glucose deprivation, which involves ATF4. ATF4 knockdown suppressed VEGF expression under glucose deprivation. Moreover, AhR knockdown suppressed VEGF and ATF4 expression under glucose deprivation at genetic and protein levels. CONCLUSIONS: The AhR-VEGF pathway through ATF4 is a novel pathway in glucose-deprived liver cancer cells that is related to the microenvironment within a cancer tissue affecting liver cancer malignancy

Methamphetamine induces endoplasmic reticulum stress related gene CHOP/Gadd153/ddit3 in dopaminergic cells

We examined the toxicity of methamphetamine and dopamine in CATH.a cells, which were derived from mouse dopamine-producing neural cells in the central nervous system. Use of the quantitative real-time polymerase chain reaction revealed that transcripts of the endoplasmic reticulum stress related gene (CHOP/Gadd153/ddit3) were considerably induced at 24–48 h after methamphetamine administration (but only under apoptotic conditions), whereas dopamine slightly induced CHOP/Gadd153/ddit3 transcripts at an early stage. We also found that dopamine and methamphetamine weakly induced transcripts for the glucose-regulated protein 78 gene (Grp78/Bip) at the early stage. Analysis by immunofluorescence microscopy demonstrated an increase of　CHOP/Gadd153/ddit3 and Grp78/Bip proteins at 24 h after methamphetamine administration. Treatment of CATH.a cells with methamphetamine caused a re-distribution of dopamine inside the cells, which mimicked the presynaptic activity of neurons with cell bodies located in the ventral tegmental area or the substantia nigra. Thus, we have demonstrated the existence of endoplasmic reticulum stress in a model of presynaptic dopaminergic neurons for the first time. Together with the recent evidence suggesting the importance of presynaptic toxicity, our findings provide new insights into the mechanisms of dopamine toxicity, which might represent one of the most important mechanisms of methamphetamine toxicity and addiction

Forum Minireview Proof of the Mysterious Efficacy of Ginseng: Basic and Clinical Trials: Suppression of Adrenal Medullary Function In Vitro by Ginseng

Abstract. The root of Panax ginseng C.A. MEYER has been reported to have an anti-stress action. Therefore, the effects of ginseng components on functions of adrenal medulla, which is one of the most important organs responsive to stress, were investigated in vitro. First, the components of ginseng were mainly divided into two fractions, that is, the saponin-rich and non-saponin fractions. The saponin-rich fraction greatly reduced the secretion of catecholamines from bovine adrenal chromaffin cells stimulated by acetylcholine (ACh), whereas the nonsaponin fraction did not affect it at all. The protopanaxatriol-type saponins inhibited the AChevoked secretion much more strongly than the protopanaxadiol-type. On the other hand, only one oleanane-type saponin, ginsenoside-Ro, had no such effect. Recent reports have demonstrated that the saponins in ginseng are metabolized and absorbed in digestive tracts following oral administration of ginseng. All of the saponin metabolites greatly reduced the ACh-evoked secretion. M4 was the most effective inhibitor among the metabolites. M4 blocked ACh-induced Na + influx and ion inward current into the chromaffin cells and into the Xenopus oocytes expressing human a 3b4 nicotinic ACh receptors, respectively, suggesting that the saponin metabolites modulate nicotinic ACh receptors followed by the reduction of catecholamine secretion. It is highly possible that these effects of ginsenosides and their metabolites are associated with the anti-stress action of ginseng

Objective evaluation of chemotherapy-induced peripheral neuropathy using quantitative pain measurement system (Pain Vision®), a pilot study

Abstract Background In an evaluation of chemotherapy-induced peripheral neuropathy (CIPN), objectivity may be poor because the evaluation is determined by the patient’s subjective assessment. In such cases, management of neuropathy may be delayed and CIPN symptoms may become severe. In this pilot study, we attempted an objective evaluation of CIPN using a quantitative pain measurement system (Pain Vision®). Methods The subjects were patients with gynecologic cancer who underwent chemotherapy using taxane and platinum drugs. The grade of the peripheral sensory nerve disorder was based on the Common Terminology Criteria for Adverse Events (CTC-AE) ver. 4.0 and was evaluated before the initiation of therapy and up to six chemotherapy cycles. A symptom scale assessed by the patients using a peripheral neuropathy questionnaire (PNQ) was also evaluated. Simultaneously during these evaluations, graded electric current was applied from the probe to a fingertip and measured both the lowest perceptible current and lowest current perceived as pain by Pain Vision®. From these values, the pain degree was calculated from the following formula: (pain perception current value - lowest perceptible current value) ÷ lowest perceptible current value × 100. We compared the pain degrees by Pain Vision® during CIPN development with the value obtained before chemotherapy initiation. Results Forty-one patients were enrolled. In the evaluation by a medical professional, 28 (64.3%) patients developed CIPN during 2.5 ± 1.1 chemotherapy cycles (mean ± standard deviation). The pain degree by Pain Vision® at grade 1 and 2 CIPN development according to the evaluation (CTC-AE) was significantly decreased compared to that before chemotherapy initiation (126.0 ± 114.5 vs. 69.8 ± 46.8, p = 0.001, and 126.0 ± 114.5 vs. 32.8 ± 32.6, p = 0.004). Changes in the pain degree by Pain Vision® were also found during scale B and C, D CIPN development in the patient evaluation (PNQ) (115.9 ± 112.4 vs. 70.6 ± 56.5, p = 0.005, and 115.9 ± 112.4 vs. 46.3 ± 42.9, p = 0.004). In the 13 patients in whom CIPN did not occur, no significant decrease in the pain degree by Pain Vision® was detected (p = 0.764). There was no discontinuation of the measurements because of adverse events such as discomfort from the electric current. Conclusion The decrease in the pain degree measured by Pain Vision® was associated with the onset of CIPN symptoms. Particularly, detection of CIPN by Pain Vision® was possible, though most of the CIPN that occurred was low grade or mild symptom. Pain Vision® might become a noninvasive and convenient objective CIPN detection tool to supplement subjective CIPN evaluation. Trial registration The study approval number in the institution; H25–140. Registered December 17, 2013

Development and evaluation of adsorption sheet (HD safe sheet-U) using active carbon for the purpose of the preventing the contamination diffusion of urinary excreted anticancer drug

Abstract Background Certain amount of anticancer drugs is excreted in the urine of patients receiving anticancer drugs, and urinary scattering including anticancer drugs at excretion has become a route of anticancer drug contamination. Therefore, we developed an active carbon sheet (HD safe sheet-U) that prevented diffusion by adsorbing anticancer drugs including that excreted in urine. The present study conducted a performance evaluation of this sheet. Methods The adsorption performance of active carbon to anticancer drug in the urine was evaluated by determining concentration changes in the active carbon suspension (5 mg/mL) of 14 kinds of anticancer drugs (cyclophosphamide, ifosfamide, carboplatin, cisplatin, methotrexate, 5-fluorouracil, cytarabine, gemcitabine, doxorubicin, epirubicin, paclitaxel, docetaxel, etoposide, and irinotecan) diluted with artificial urine. Adhesion of the anticancer drug dropping on the sheet to a slipper sole was evaluated because urine including anticancer drugs is scattered on the floor, which can spread by adhering to shoe soles of patients and healthcare workers. The performance of the active carbon sheet was compared with two other types of medical adsorption sheets used as control sheets. Anticancer drugs diluted with artificial urine (1 mL) were dropped on the active carbon sheet and the two control sheets. The sheets were trod with slippers made by polyvinyl chloride. The adhered anticancer drug was wiped off and its quantity was determined. Results A remarkable decrease in anticancer drug concentrations, except for cisplatin, was detected by mixture of active carbon in the artificial urine (0–79.6%). The quantity of anticancer drug adhesion to slipper soles from the active carbon sheet was significantly lower compared with that observed for the two control sheets for eight kinds of anticancer drugs (cyclophosphamide, ifosfamide, carboplatin, methotrexate, cytarabine, gemcitabine, doxorubicin, and docetaxel). There was no adhesion in cyclophosphamide and docetaxel. Furthermore, the quantities of adhesion in cytarabine, gemcitabine, doxorubicin, paclitaxel, and irinotecan were lower than determination limit. Conclusion Active carbon might be effective in adsorbing urinary anticancer drugs. The active carbon sheet adsorbed urinary excreted anticancer drugs, and use of such sheets might prevent diffusion of contamination due to urinary excreted anticancer drugs

The efficacy of sodium azulene sulfonate L-glutamine for managing chemotherapy-induced oral mucositis in cancer patients: a prospective comparative study

Abstract Background The efficacy of sodium azulene sulfonate L-glutamine (GA) in treating oral mucositis caused by the administration of anticancer agents has not been previously elucidated. Therefore, this prospective comparative study was conducted to evaluate the efficacy of GA in treating oral mucositis caused by chemotherapy regimens involving fluorinated pyrimidine anticancer drugs. Methods The subjects of this study were patients with oral mucositis of grade 2 or higher while on outpatient chemotherapy regimens involving fluorinated pyrimidine anticancer drugs for colorectal or breast cancer. The subjects were randomly divided into a group that received GA (the GA group) or a group that did not receive GA (the control group) by using the closed-envelope method. GA was administered three times a day every day from the first day of the regimen until the final day. The primary endpoint was the development of oral mucositis of grade 2 or higher. The secondary endpoint was the severity of oral pain, which was judged using an 11-stage numerical rating scale (NRS) ranging from 0 to 10. Results The proportion of patients with oral mucositis of grade 2 or higher was 32.4% in the GA group and 57.6% in the control group. The GA group had a significantly lower frequency of occurrence. The changes in the NRS scores before and after the trial began were − 2.9 ± 0.6 in the GA group and − 1.2 ± 0.5 in the control group. The NRS score decreased more significantly in the GA group than in the control group (P = 0.046). One patient stopped GA treatment voluntarily due to nausea; other than nausea, no GA-related side effects were observed. Conclusions GA protects against oral mucositis and reduces the severity of prevailing oral mucositis symptoms. Our findings indicate that GA is a highly safe and convenient drug