The clinical effect of an electric massage chair on chemotherapy-induced nausea and vomiting in cancer patients: randomized phase II cross-over trial.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse events in cancer patients and can negatively affect their quality of life (QoL). This study aimed to evaluate the clinical efficacy of an electric massage chair (EMC) for the treatment of CINV. METHODS: A randomized phase II cross-over trial was conducted on solid cancer patients who received moderate (MEC) to high emetogenic chemotherapy (HEC). The participants were randomly assigned to receive their first chemotherapy either on a standard bed (Group A) or in an EMC (Group B) during the infusion. The patients were then crossed over to the next cycle. CINV and QoL questionnaires were collected from the participants. RESULTS: A total of 59 patients completed the trial protocol and were included in the analysis, with 29 and 30 patients in Groups A and B, respectively. The mean INVR (Index of Nausea, Vomiting, and Retching) score in the 2nd day of the first cycle was higher in Group B (3.63 ± 5.35) than Group A (2.76 ± 4.78), but the difference was not statistically significant (p = 0.5367). The complete response rate showed little difference between the groups. Among the high-emetic risk subgroups, patients who received HEC (p = 0.04595), younger patients (p = 0.0108), and non-colorectal cancer patients (p = 0.0495) presented significantly lower CINV scores when EMC was applied. CONCLUSION: Overall, there was no significant difference in INVR scores between standard care and EMC. Applying EMC at the first chemotherapy infusion may help preserve QoL and reduce CINV in high-risk patients. TRIAL REGISTRATION: KCT0008200, 17/02/2023, Retrospectively registered.

Optimal harvest-time to maximize the annual camptothecin production by Ophiorrhiza pumila in a plant factory with artificial light.

Ophiorrhiza pumila is a medicinal plant that grows in subtropical forests and produces camptothecin (CPT). To determine an optimal harvest time of O. pumila in a plant factory with artificial light (PFAL), we investigated the CPT distribution in each organ and at the developmental stage and estimated the annual CPT production. For this study, the O. pumila plants were grown in controlled environments (16 h light period, photosynthetic photon flux density of 100 µmol m-2 s-1 under white light-emitting diode lamps, air temperature of 28 °C, relative humidity of 80%, and CO2 concentration of 1000 µmol mol-1). First, the stem, root, and seed pod had higher CPT contents than the leaves, flower, and ovary. The optimal harvest time of O. pumila in a PFAL was 63 days after transplanting (DAT), because the CPT content in the whole organs was the highest at the seed-ripening stage. Second, based on these results, the estimated annual CPT production of O. pumila cultivated in a PFAL was 380 mg m-2 y-1 (63 DAT). This value was 4.3 times greater than the annual CPT production by Camptotheca acuminata in a greenhouse. We concluded that the CPT production by O. pumila in a PFAL throughout the year has many advantages, although the demand for electrical energy was high compared to that of Camptotheca acuminata in a greenhouse.

Herbal Medicine for Patients with Cognitive Impairment: An Observational Study.

PURPOSE: The potential effects of herbal medicine for patients with cognitive disorders have been reported in various human and animal studies. This study aimed to explore the effect of herbal medicine treatment according to the Korean Medicine (KM) pattern identification for patients with mild cognitive impairment and early dementia. PATIENTS AND METHODS: Twenty patients with mild cognitive impairment or mild dementia who planned to receive herbal medicine treatment were enrolled. Herbal formulae were prescribed based on the KM pattern for 12-24 weeks. Seoul Neuropsychological Screening Battery II (SNSB-II) and Montreal Cognitive Assessment (MoCA) were assessed at the baseline, after 12 weeks, and after 24 weeks (Trial registration: cris.nih.go.kr, KCT0004799). RESULTS: Herbal medicine products, including Yukmijihwang-tang, Samhwangsasim-tang, Palmul-tang, Banhasasim-tang, and Yukgunja-tang, were prescribed to the patients. Among the SNSB-II five cognitive function domains, the T scores for language, visuospatial function, memory, and frontal/executive function increased over time. The MoCA score also improved following the treatment (mean difference 4.23 [95% CI: 2.60, 5.86], p < 0.0001 at 12-week follow-up compared to the baseline). Considering the KM pattern scores, phlegm-dampness and fire-heat scores tended to improve after the treatment. No serious adverse events related to the intervention were reported. CONCLUSION: The potential effect of herbal medicine formulae products on improving cognitive functions in patients with cognitive impairment was observed. Further research is needed to objectify the KM pattern identification process and evaluate the KM pattern-related signs and symptoms.

Efficacy of Jihwangeumja (Dihuang Yinzi) on cognitive function and activities of daily living in patients with Alzheimer disease: A protocol for a systematic review and meta-analysis.

BACKGROUND: This systematic review protocol describes the methods proposed to evaluate the efficacy and safety of Jihwangeumja in patients with Alzheimer disease. METHODS: The following databases, PubMed, EMBASE, CENTRAL, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, National Digital Science Library, Korean Information Service System, and Korean Medical Database will be searched for relevant publications without language or publication status restrictions. Search terms will be based on "Alzheimer" for participants and "Jihwangeumja" or "Dihuang Yinzi" for interventions. Two researchers will independently extract the study data from the included studies and only randomized controlled trials will be included. The risk of bias will also be assessed independently by 2 researchers using the Cochrane risk of bias tool. We will use RevMan software random-effects and fixed-effect models for the assessment of heterogeneity and data synthesis. Any changes in the plan for documenting significant protocol amendments will require the researchers to have a revision agreement and register the international prospective register of systematic review modification. RESULTS: The treatment effect and safety will be measured by meta-analysis and the quality of the included studies will be reviewed. CONCLUSION: This systematic review will provide evidence regarding the efficacy and safety of Jihwangeumja. ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data will not be included in this paper. The study findings will be disseminated through conference presentations. OSF REGISTRATION: DOI: 10.17605/OSF.IO/HXA58.

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Effects of Concentration and Temperature of Nutrient Solution on Growth and Camptothecin Accumulation of Ophiorrhiza pumila.

The medicinal plant, Ophiorrhiza pumila, naturally grows on the floors of humid inland forests in subtropical areas. It accumulates camptothecin (CPT), which is used as an anti-tumor agent, in all organs. We investigated the optimal hydroponic root-zone environments for growth and CPT accumulation in O. pumila in a plant factory. In experiment 1, to determine the appropriate nutrient solution concentration (NSC), O. pumila was cultivated using four concentrations (0.125, 0.25, 0.5, and 1.0 times) of a commercial solution for 63 days after the start of treatment (DAT). The electrical conductivity of these NSCs was 0.6, 0.9, 1.5, and 2.7 dS m-1, respectively. The total dry weights at 0.25 and 0.5 NSCs were higher than those at the other two NSCs. CPT content at 0.25 NSC was significantly higher than those at other NSCs. In experiment 2, to investigate an appropriate nutrient solution temperature (NST), O. pumila was cultivated at four NSTs (10, 20, 26, and 35 °C, named as T10, T20, T26, and T36, respectively) for 35 DAT. The growth and CPT content at T20 was the highest among the treatments. Therefore, root-zone environments of 0.25 NSC and 20 °C of NST produced the best growth and CPT accumulation in O. pumila.

Safety and efficacy of Jujadokseo-hwan for memory deficit (amnesia) in mild neurocognitive disorder: A protocol for randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial.

BACKGROUND: Mild neurocognitive disorder (mNCD) is one of the degenerative diseases that results in memory deficit, and can progress to dementia. The effectiveness of drug therapy for mNCD is still debatable, but treatment of this disease has important implications for postponing or preventing dementia. Jujadokseo-hwan (JDH) is a traditional herbal medicine formulation that exhibits improvement in cognitive abilities and neuroprotective effects. In this study, we will evaluate the safety and efficacy of JDH compared to placebo in mNCD patients. METHODS AND DESIGN: This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial. After obtaining informed consent from all participants and performing the screening process, the participants will be equally divided into an experimental group and a control group. Each participant will visit the trial center 7 times during the 12 weeks of intervention. The follow up study will be conducted 12 weeks after the intervention ends. The primary outcome is the variance in Seoul verbal learning test-elderly's version (SVLT-E) score from baseline to 12 weeks. Secondary outcomes include scores/values for the following variables: SVLT-E, Rey complex figure test, Digit span test, Korean-Boston naming test, calculation ability, controlled oral word association test, Korean-color word stroop test, digit symbol coding, Korean-trail making test-elderly's version, Korean version of mini mental state examination for dementia screening, euro-qol-5 dimension, pattern identifications tool for cognitive disorders, Korean version of Montreal cognitive assessment, Korean quality of life-Alzheimer disease, computerized tongue image analysis system, blood pressure pulse analyzer, bioelectrical impedance analyzer, wearable electroencephalogram device, functional near-infrared spectroscopy system, and cost analysis. DISCUSSION: This is the first trial evaluating the efficacy of JDH for mNCD. We expect this trial will provide strong support for wide use of JDH for mNCD and lead to further research on herbal medicine treatments for mNCD. TRIAL REGISTRATION NUMBER: KCT0003570 (Registered in Clinical Research Information Service of the Republic of Korea, https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=12669).

Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease.

OBJECTIVE: Supplementation with serine attenuates alcoholic fatty liver by regulating homocysteine metabolism and lipogenesis. However, little is known about serine metabolism in fatty liver disease (FLD). We aimed to investigate the changes in serine biosynthetic pathways in humans and animal models of fatty liver and their contribution to the development of FLD. METHODS: High-fat diet (HFD)-induced steatosis and methionine-choline-deficient diet-induced steatohepatitis animal models were employed. Human serum samples were obtained from patients with FLD whose proton density fat fraction was estimated by magnetic resonance imaging. 3-Phosphoglycerate dehydrogenase (Phgdh)-knockout mouse embryonic fibroblasts (MEF) and transgenic mice overexpressing Phgdh (Tg-phgdh) were used to evaluate the role of serine metabolism in the development of FLD. RESULTS: Expression of Phgdh was markedly reduced in the animal models. There were significant negative correlations of the serum serine with the liver fat fraction, serum alanine transaminase, and triglyceride levels among patients with FLD. Increased lipid accumulation and reduced NAD+ and SIRT1 activity were observed in Phgdh-knockout MEF and primary hepatocytes incubated with free fatty acids; these effects were reversed by overexpression of Phgdh. Tg-Phgdh mice showed significantly reduced hepatic triglyceride accumulation compared with wild-type littermates fed a HFD, which was accompanied by increased SIRT1 activity and reduced expression of lipogenic genes and proteins. CONCLUSIONS: Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.

Efficacy and safety of oral SOCG in treatment of major depressive disorder: A protocol for a phase II, randomized, double-blind, placebo controlled, parallel-groups, dose finding exploratory study.

INTRODUCTION: Major depressive disorder (MDD) is a common condition worldwide, and leads to degradation in quality of life and large socioeconomic costs. There has been increasing demand for new therapies with fewer side effects. SOCG (SOCG tablet) is a modified prescription of So-ochim-tang, which is widely used in Traditional Korean Medicine to treat MDD. We aim to evaluate the efficacy of SOCG in treating MDD, and identify the optimum dose. DESIGN: The protocol we are following is that of a Phase II clinical trial with a randomized, double blinded, placebo controlled, and parallel design. One hundred forty-eight participants will be randomly divided into 4 groups and treated for 8 weeks. OUTCOME MEASURES: The primary outcome will be the score in the Korean Version of the Hamilton Depression Rating Scale. Scores in the Korean version of the Beck Depression Inventory-II Korean Symptom Check List-95 (KSCL-95), State Trait Anxiety Inventory-Korean version, State- Trait Anger Expression Inventory- Korean version (STAXI-K), Insomnia Severity Index (ISI), and the EuroQol-5 Dimension (EQ-5D) will be considered as secondary outcomes. DISCUSSION AND CONCLUSIONS: Demonstration of human safety and efficacy of SOCG in the present trial and identification of the appropriate dose will justify a New Drug Application and a phase III clinical trial. Further, we expect that this new antidepressant will be able to increase cure rates, and alleviate the burden of medical expenses. TRIAL REGISTRATION NUMBER: Clinical Research Information Service, Republic of Korea (KCT0002763).

Label-free quantitative proteomic analysis of Panax ginseng leaves upon exposure to heat stress.

BACKGROUND: Ginseng is one of the well-known medicinal plants, exhibiting diverse medicinal effects. Its roots possess anticancer and antiaging properties and are being used in the medical systems of East Asian countries. It is grown in low-light and low-temperature conditions, and its growth is strongly inhibited at temperatures above 25°C. However, the molecular responses of ginseng to heat stress are currently poorly understood, especially at the protein level. METHODS: We used a shotgun proteomics approach to investigate the effect of heat stress on ginseng leaves. We monitored their photosynthetic efficiency to confirm physiological responses to a high-temperature stress. RESULTS: The results showed a reduction in photosynthetic efficiency on heat treatment (35°C) starting at 48 h. Label-free quantitative proteome analysis led to the identification of 3,332 proteins, of which 847 were differentially modulated in response to heat stress. The MapMan analysis showed that the proteins with increased abundance were mainly associated with antioxidant and translation-regulating activities, whereas the proteins related to the receptor and structural-binding activities exhibited decreased abundance. Several other proteins including chaperones, G-proteins, calcium-signaling proteins, transcription factors, and transfer/carrier proteins were specifically downregulated. CONCLUSION: These results increase our understanding of heat stress responses in the leaves of ginseng at the protein level, for the first time providing a resource for the scientific community.

Physciosporin suppresses the proliferation, motility and tumourigenesis of colorectal cancer cells.

BACKGROUND: Lichens, which represent symbiotic associations of fungi and algae, are potential sources of numerous natural products. Physciosporin (PHY) is a potent secondary metabolite found in lichens and was recently reported to inhibit the motility of lung cancer cells via novel mechanisms. PURPOSE: The present study investigated the anticancer potential of PHY on colorectal cancer (CRC) cells. METHODS: PHY was isolated from lichen extract by preparative TLC. The effect of PHY on cell viability, motility and tumourigenicity was elucidated by MTT assay, hoechst staining, flow cytometric analysis, transwell invasion and migration assay, soft agar colony formation assay, Western blotting, qRT-PCR and PCR array in vitro as well as tumorigenicity study in vivo. RESULTS: PHY decreased the viability of various CRC cell lines (Caco2, CT26, DLD1, HCT116 and SW620). Moreover, PHY elicited cytotoxic effects by inducing apoptosis at toxic concentrations. At non-toxic concentrations, PHY dose-dependently suppressed the invasion, migration and colony formation of CRC cells. PHY inhibited the motility of CRC cells by suppressing epithelial-mesenchymal transition and downregulating actin-based motility markers. In addition, PHY downregulated ß-catenin and its downstream target genes cyclin-D1 and c-Myc. Moreover, PHY modulated KAI1 C-terminal-interacting tetraspanin and KAI1 expression, and downregulated the downstream transcription factors c-jun and c-fos. Finally, PHY administration showed considerable bioavailability and effectively decreased the growth of CRC xenografts in mice without causing toxicity. CONCLUSION: PHY suppresses the growth and motility of CRC cells via novel mechanisms.

Expression of Genes in Primo Vasculature Floating in Lymphatic Endothelium Under Lipopolysaccharide and Acupuncture Electric Stimulation.

It is known that the primo vascular system (PVS) includes the primo nodes and vessels. However, the relevant genes in the PVS system for both pathologic and physiologic condition are poorly understood. Here, we first examined the gene expression in primo vessels (PVs) floating in lymphatic endothelium by isolation of PVS and lymphatic vessels (LVs) containing PVS. To investigate therapeutic effects, both PVs and LVs containing PVS were isolated after lipopolysaccharide injection and acupuncture electric stimulation at two acupoints Joksamni (ST36) and Hapgok (LI04) following lipopolysaccharide injection. We used reverse transcriptase-polymerase chain reaction to examine expression of lymphatic endothelial cell markers and inflammatory related genes. We found that lymphatic endothelial cell markers such as fms-related tyrosine kinase 4 (Flt4), lymphatic vessel endothelial receptor (Lyve-1), prospero homeobox protein 1 (Prox-1), and podoplanin (Pdpn) were highly expressed in PV compared to that of lymphatic endothelium, suggesting pivotal roles of PV in LV under inflammation. Furthermore, lymphatic-related genes including metal-response element-binding transcription factor 2 (Mtf2), hypoxia inducible factor (Hif1a), angiotensin II type 1 receptor (Agtr1), and angiotensin II type 2 receptor (Agtr2) were also overall increased in PV, and remarkably increased and these genes except peroxisome proliferator-activated receptor gamma (Pparg) after acupuncture electric stimulation in two acupoints implying central role of PV by gene activation.

Meditation-based clinical study to determine the correlation of quantitative electroencephalogram (qEEG) and 24-hour EEG activity.

BACKGROUND: The heart continuously transmits information to the cerebrum during each pulse, and influences information processing such as perception, cognition, and emotion, which are processed in the cerebrum. This is the basis for the theory of oriental medicine widely used in psychiatric medicine and clinical practice, so-called Simjushinji (heart and brain) theory, that the heart controls the mind. The present study aims to analyze the correlation between heart and brain function by 24-hour active electrocardiogram and quantitative electroencephalogram (EEG) measurement under meditation. METHODS: This randomized, controlled, assessor-blinded, 2-armed, parallel, multicenter clinical trial will analyze a total of 50 subjects, including 25 each for the test group and the active control group. Subjects will be randomly allocated to the test group (performing resource mindfulness) and the control group (performing stress mindfulness) in a 1:1 ratio. The clinical trial consists of 3 stages. The first and third stages are stable states. The second stage is divided into the test and active comparator groups. Quantitative EEG (qEEG) measurements at stages 1 and 3 will be recorded for 10 minutes; measurements at stage 2 will be recorded for 20 minutes with the eyes closed. The 24-hour Holter Monitoring and heart rate variability will be evaluated at each stage. Before the beginning of stage 3, subjects will complete the questionnaires. The primary outcome will be analyzed by independent t tests of both groups. DISCUSSION: Scientific studies based on clinical epistemology are expected to serve as a basis for sustainable medical services in the field of psychiatric medicine in Korea. HRV, blood pressure index, and biometric index in qEEG, as determined by 24-hour Holter monitoring, will complement quantitative biomarkers and be useful in various fields.

Inhibition of Cytochrome P450 by Propolis in Human Liver Microsomes.

Although propolis is one of the most popular functional foods for human health, there have been no comprehensive studies of herb-drug interactions through cytochrome P450 (CYP) inhibition. The purpose of this study was to determine the inhibitory effects of propolis on the activities of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 using pooled human liver microsomes (HLMs). Propolis inhibited CYP1A2, CYP2E1 and CYP2C19 with an IC50 value of 6.9, 16.8, and 43.1 µg/mL, respectively, whereas CYP2A6, 2B6, 2C9, 2D6, and 3A4 were unaffected. Based on half-maximal inhibitory concentration shifts between microsomes incubated with and without nicotinamide adenine dinucleotide phosphate, propolis-induced CYP1A2, CYP2C19, and CYP2E1 inhibition was metabolism-independent. To evaluate the interaction potential between propolis and therapeutic drugs, the effects of propolis on metabolism of duloxetine, a serotonin-norepinephrine reuptake inhibitor, were determined in HLMs. CYP1A2 and CYP2D6 are involved in hydroxylation of duloxetine to 4-hydroxy duloxetine, the major metabolite, which was decreased following propolis addition in HLMs. These results raise the possibility of interactions between propolis and therapeutic drugs metabolized by CYP1A2.

Suicidal ideation among postmenopausal women on hormone replacement therapy: The Korean National Health and Nutrition Examination Survey (KNHANES V) from 2010 to 2012.

BACKGROUND: Suicide is a major public health problem around the world. Some studies have found that hormone replacement therapy (HRT) is associated with depression in postmenopausal women. Depression is a well-known risk factor for suicide; therefore, we investigated the relationship between HRT and suicidal ideation in postmenopausal Korean women. METHODS: We included 2286 postmenopausal women with or without HRT from the Korean National Health and Nutrition Examination Survey 2010-2012. The use and duration of HRT and mental health status, including stress, depressive mood, and suicidal ideation and attempts, were assessed by self-report questionnaires. RESULTS: The proportion of participants with depressive mood and suicidal ideation was higher in the HRT group than the non-HRT group (all p values<0.05). As the duration of HRT increased, the percentage of participants with suicidal ideation increased (p for trend=0.006). After adjusting for all covariates, the odds ratio (95% confidence intervals) for suicidal ideation was 1.742 (1.223-2.482) in the women with HRT, compared to women without HRT. HRT duration longer than 10 years was associated with suicidal ideation (odds ratio=2.089 and 95% confidence intervals=1.069-4.084). LIMITATIONS: The cross-sectional design, a possibility of incorrect answer about menopausal status, and no assessment of the type of HRT are the main limitations of this study. CONCLUSION: Postmenopausal women receiving HRT, especially for more than 10 years, showed increased suicidal ideation compared with postmenopausal women without HRT. Physicians should pay attention to mood symptoms and suicidal ideation in postmenopausal women with HRT.

Inhibitory effects of Hwang-Ryun-Hae-Dok-Tang on cytochrome P450 in human liver microsomes.

1. The herb-drug interaction potential of Hwang-Ryun-Hae-Dok-Tang (HR) extracts mediated by cytochrome P450 (CYP) inhibition was determined using human liver microsomes. 2. HR strongly inhibited CYP1A2 and moderately inhibited CYP2C19, CYP2D6, and CYP3A4 (testosterone) but not CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 (midazolam). 3. The enzyme kinetic results suggest that CYP1A2 inhibition is competitively reversible (Ki, 13.4±1.8 µg/ml), and CYP2D6 inhibition is quasi-irreversible (KI, 0.234±0.138 µg/ml; kinact, 0.067±0.006 min(-1)). 4. Fermentation using Lactobacillus acidophilus attenuated the HR-induced inhibition of CYP2D6, but not the other isoforms. 5. Neither CYP1A2 nor CYP3A4 was markedly inhibited by berberine, palmatine, and geniposide-major components in HR-and CYP2D6 was inhibited by berberine (IC50, 13.8 µg/ml) in a metabolism-dependent manner. 6. The results suggest the possibility of HR-drug interaction through inhibition of CYP-particularly CYP2D6-which may be attenuated by fermentation using L. acidophilus.

HepG2 cells as an in vitro model for evaluation of cytochrome P450 induction by xenobiotics.

Although various in vitro assays have been developed to evaluate the cytochrome P450 (CYP)-inducing potential of drug candidates, there is a continuing need for the development of a reliable model in drug discovery. The objective of the present study was to compare CYP induction by chemicals in HepG2 cells with Huh7, NKNT-3, and reverted NKNT-3 cells. HepG2 cells showed more similarity to human liver than the other cell lines in comparisons of the expression of cellular proteins. In evaluation of basal CYP activity, Huh7 cells exhibited the highest CYP1A2 and CYP3A4 activity, and HepG2 cells showed the highest CYP2B6 activity. The inducibility of CYP1A2, CYP2B6, and CYP3A4 by prototypical inducers was determined using enzyme assay, immunoblot analysis, and real-time PCR. Among the cells tested, HepG2 cells were highly responsive to CYP inducers, such as 3-methylcholanthrene for CYP1A2 and phenobarbital for CYP2B6 and CYP3A4. Moreover, HepG2 cells were responsive to various CYP1A2, CYP2B6, and CYP3A4 inducers as determined using fluorogenic and LC-MS/MS substrates. Thus, HepG2 cells may be comparable to human hepatocytes for the evaluation of CYP induction or slightly less sensitive. These results suggest HepG2 cells as a cell-based model in screening for CYP inducers in drug discovery.

Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism.

In this study, we investigated whether gastric cancer with hypoxia-induced resistance to 5-fluorouracil (5-FU) could be re-sensitized following treatment with low-dose dichloroacetate (DCA), an inhibitor of the glycolytic pathway. The expression profiles of hypoxia-inducible factor-1α (HIF-1α) and pyruvate dehydrogenase kinase-1 (PDK-1) were analyzed in tissues from 10 patients with gastric cancer who had different responses to adjuvant 5-FU treatment. For the in vitro assays, cell viability and apoptosis were evaluated with and without treatment with 20mM DCA in the AGS and MKN45 cell lines, as well as in PDK1 knockdown cell lines. The expression levels of HIF-1α and PDK-1 were both elevated in the tumor tissues relative to the normal gastric tissues of most patients who showed recurrence after adjuvant 5-FU treatment. Cellular viability tests showed that these cell lines had a lower sensitivity to 5-FU under hypoxic conditions compared to normoxic conditions. Moreover, the addition of 20mM DCA only increased the sensitivity of these cells to 5-FU under hypoxic conditions, and the resistance to 5-FU under hypoxia was also attenuated in PDK1 knockdown cell lines. In conclusion, DCA treatment was able to re-sensitize gastric cancer cells with hypoxia-induced resistance to 5-FU through the alteration of glucose metabolism.

In vitro and in vivo assessment of cytochrome P450-mediated herb-drug interaction of Ssang-hwa-tang.

We have evaluated the herb-drug interaction potential of Ssang-hwa-tang (SHT) mediated by cytochrome P450 (CYP) inhibition/induction. Further, the effects of fermentation on the CYP-mediated herb-drug interaction potential were determined. SHT showed inhibitory activity toward CYP1A2, but not 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes. The results of the enzyme kinetic study suggested that the SHT-induced CYP1A2 inhibition is mixed reversible inhibition. The hepatic CYP expression and activity in rats treated with SHT were examined. The expression/activity of CYP2E1 increased as a result of SHT extract treatment (P<0.005 or P<0.001, respectively), which raises the possibility that SHT may increase the toxicity of environmental toxicants through the elevation of CYP2E1-mediated metabolic activation. SHT fermentation using Lactobacillus fermentum or Lactobacillus gasseri resulted in attenuation of the SHT-induced CYP1A2 inhibition, but not CYP2E1 induction, suggesting that changes in the chemical composition of SHT through fermentation can affect the inhibition of CYP1A2 activity.