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Background: In order for general practice / family medicine clerkships to be improved in undergraduate medical education, it is necessary to clarify the impacts of general practice / family medicine clerkships. Using text mining to analyze the reflective writing of medical students may be useful for further understanding the impacts of clinical clerkships on medical students. Methods: The study involved 125 fifth-year Fukushima Medical University School of Medicine students in the academic year 2018-2019. The settings were three clinics and the study period was 5 days. The clerkships included outpatient and home visits. Students' reflective writing on their clerkship experience was collected on the final day. Text mining was used to extract the most frequent words (nouns) from the reflective writing. A co-occurrence network map was created to illustrate the relationships between the most frequent words. Results: 124 students participated in the study. The total number of sentences extracted was 321 and the total number of words was 10,627. The top five frequently-occurring words were patient, home-visit, medical practice, medical care, and family. From the co-occurrence network map, a co-occurrence relationship was recognized between home-visit and family. Conclusion: Data suggest that medical students may learn the necessity of care for the family as well as the patient in a home-care setting.

Lycopene is a lipophilic unsaturated carotenoid exhibiting a strong singlet oxygen-quenching ability. Herein, we investigated the effect of lycopene intake on the fasting blood glucose (FBG) level by conducting a systematic review and meta-analyses. We searched 15 databases (from the earliest date to June 2022 for PubMed or to August or September 2018 for the other databases) and included human interventional studies that assessed the effects of oral lycopene intake on FBG levels of participants ≥ 18 years of age. Three authors independently selected applicable studies and then assessed the study quality. Data were pooled as standardized mean difference (SMD) and analyzed by the random-effects model. Heterogeneity was assessed by I2 statistics. A meta-analysis including 11 trial arms (n = 750) revealed a tendency towards a significant decrease in FBG level with not-important heterogeneity [SMD = −0.15 (95% CI: −0.31, 0.00), p = 0.05, I2 = 9%]. Subgroup meta-analysis including two studies (n = 152) in type 2 diabetes patients revealed significantly decreased FBG levels with not-important heterogeneity [SMD = −0.37 (95% CI: −0.69, −0.05), p = 0.02, I2 = 0%]. Most studies meeting the eligibility criteria had a moderate risk of bias. The funnel plot for FBG suggested an absence of publication bias. In conclusion, this systematic review and meta-analyses suggested that lycopene intake exerted an FBG-decreasing effect.

The aims of this study were to identify sensory processing profiles specific to preschoolers with DCD in a community sample and examine the association of sensory processing problems with motor coordination difficulties in these children. Sixty-three 5-year-old children with DCD and without other neurodevelopmental disorders and 106 age-matched typically developing children participated in this study. Sensory processing problems were assessed using the Sensory Profile. Our results demonstrated problems in wide sensory processing patterns (low registration, sensitivity and avoiding) and areas (auditory, vestibular, touch and oral) in children with DCD compared with typically developing children. Additionally, the association of problems in sensory processing patterns (sensitivity and avoiding) and areas (touch and auditory) with motor coordination difficulties were identified in children with DCD alone. Our findings indicate that sensory processing abnormalities may contribute to the pathophysiology of DCD, suggesting the importance of assessing sensory processing functions in children with DCD. Electronic supplementary material The online version of this article (10.1007/s10578-020-01013-5) contains supplementary material, which is available to authorized users.

Aims/Introduction Insomnia is associated with type 2 diabetes mellitus, and results in a low quality of life. There are several known relationships between insomnia and personality. Thus, we clarified the association between some personality traits and insomnia among Japanese type 2 diabetes mellitus patients. Materials and Methods The participants were 504 type 2 diabetes mellitus patients (mean age 63.9 ± 12.5 years). Sleep disturbance and personality traits were evaluated using the Pittsburgh Sleep Quality Index‐Japanese version and the Ten‐Item Personality Inventory Japanese version, respectively. Lifestyle factors, glycated hemoglobin levels and depressive status of the patients were also included in the analyses. Results Among the 504 participants with type 2 diabetes mellitus, 154 (30.6%) showed probable insomnia. After adjustment for confounders, being female, living alone, high body mass index and “high neuroticism” were found to be significantly correlated with current insomnia. No other relationships between insomnia and glycated hemoglobin or lifestyle factors, such as smoking, drinking alcohol or exercise frequency, were found. Conclusions The prevalence of insomnia in individuals with type 2 diabetes mellitus was high, and the risk factors included some personality factors. Future prospective studies are required to confirm the therapeutic effects of behavioral interventions for insomnia in patients with type 2 diabetes mellitus.

Natsumi Tarakita,1,2 Kazutaka Yoshida,1 Norio Sugawara,3 Kazutoshi Kubo,1,4 Hanako Furukori,5 Akira Fujii,2 Kazuhiko Nakamura,1 Norio Yasui-Furukori1 1Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan; 2Department of Mental Health, Mutsu City Hospital, Mutsu, Japan; 3Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 4Department of Neuropsychiatry, Hirosaki-Aiseikai Hospital, Hirosaki, Japan; 5Department of Neuropsychiatry, Kuroishi-Akebono Hospital, Kuroishi, Japan Objectives: To determine whether etiological beliefs are different among schizophrenia patients, their family, and medical staff. Patients and methods: A cross-sectional study was performed at five hospitals and one mental clinic and included 212 patients, 144 family members, and 347 medical staff other than psychiatrists. A questionnaire about the possible etiological causes of schizophrenia was used. Results: There were significant differences in response scores among the three groups on using Angermeyer’s and Goulding’s classifications. Factor analyses revealed the following four subscales: Psychosocial, Biological, Environmental, and Cultural connotations. The structure varied among patients, family, and medical staff. Conclusion: The perspectives of schizophrenia etiology were different among patients, family, and medical staff. Keywords: schizophrenia, etiology, perception, family, caregivers, beliefs, etiological causes, patients, medical staff

Lycopene is a lipophilic unsaturated carotenoid and has a very strong singlet oxygen-quenching ability. Increased serum or plasma lycopene levels have been reported to be associated with a lower risk of metabolic syndrome. We aimed to investigate the effects of lycopene intake on blood HDL-cholesterol (HCL-c) and triglyceride (TG) levels, which are metabolic syndrome biomarkers, by systematic review and meta-analyses of human interventional trials. We searched 15 databases and included studies that assessed the effects of oral lycopene intake on blood HDL-c and TG levels of participants ≥18 years of age. Three reviewers independently selected applicable studies, then assessed study qualities. Data were pooled as standardized mean difference (SMD) and analyzed by random-effects model. Heterogeneity was assessed by I2 statistics. Meta-analysis including 12 trial arms (n = 781) revealed a significantly increased HDL-c level in the lycopene group compared with that in the control group (SMD = 0.33 [95% CI: 0.12, 0.54], p = 0.002) and moderate heterogeneity (I2 = 45%). Most subgroup meta-analyses (restricted to study design, test food type, intake period, and participants' characteristics) showed similar results for HDL-c level. On the other hand, meta-analysis including 11 studies (n = 854) revealed no significant difference in TG level between the lycopene and control groups. Most studies which met eligibility criteria had moderate risk of bias. Funnel plots for HDL-c and TG suggested an absence of publication bias. In conclusion, this systematic review and meta-analyses suggested that lycopene intake significantly improved blood HDL-c levels but not TG levels.

Background Xylitol is an approved food additive that is widely used as a sweetener in many manufactured products. It is also used in pharmaceuticals. Secondary oxalosis resulting from high dietary oxalate has been reported. However, reported cases of oxalosis following xylitol infusion are rare. Case presentation A 39-year-old man with a 16-year history of organic psychiatric disorder was hospitalized for a laparoscopic cholecystectomy because of cholecystolithiasis. He had been treated with several antipsychotics and mood stabilizers, including lithium. The patient had polyuria (> 4000 mL/day) and his serum sodium levels ranged from 150 to 160 mmol/L. Urine osmolality was 141 mOsm/L, while serum arginine vasopressin level was 6.4 pg/mL. The patient was diagnosed with nephrogenic diabetes insipidus (NDI), and lithium was gradually discontinued. Postoperative urine volumes increased further to a maximum of 10,000 mL/day, and up to 10,000 mL/day of 5% xylitol was administered. The patient’s consciousness level declined and serum creatinine increased to 4.74 mg/dL. This was followed by coma and metabolic acidosis. After continuous venous hemodiafiltration, serum sodium improved to the upper 140 mmol/L range and serum creatinine decreased to 1.25 mg/dL at discharge. However, polyuria and polydipsia of approximately 4000 mL/day persisted. Renal biopsy showed oxalate crystals and decreased expression of aquaporin-2 (AQP2) in the renal tubules. Urinary AQP2 was undetected. The patient was discharged on day 82 after admission. Conclusions Our patient was diagnosed with lithium-induced NDI and secondary oxalosis induced by excess xylitol infusion. NDI became apparent perioperatively because of fasting, and an overdose of xylitol infusion led to cerebrorenal oxalosis. Our patient received a maximum xylitol dose of 500 g/day and a total dose of 2925 g. Patients receiving lithium therapy must be closely monitored during the perioperative period, and rehydration therapy using xylitol infusion should be avoided in such cases.

Kazutaka Yoshida,1 Hideyuki Otaka,2 Hiroshi Murakami,2 Hirofumi Nakayama,1 Masaya Murabayashi,2 Satoru Mizushiri,2 Koki Matsumura,2 Jutaro Tanabe,2 Yuki Matsuhashi,2 Miyuki Yanagimachi,2 Norio Sugawara,3 Kazuhiko Nakamura,1 Makoto Daimon,2 Norio Yasui-Furukori1 1Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; 2Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; 3Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan Purpose: Insomnia, which is associated with type 2 diabetes mellitus (DM), results in a low quality of life, and several relationships exist between insomnia and coping style. Thus, we clarified the association between some coping styles and insomnia among Japanese type 2 DM patients. Subjects and methods: The subjects included 503 type 2 DM patients (mean age 63.9±12.5years). Sleep disturbance and personality traits were evaluated using the Japanese version of the Pittsburgh Sleep Quality Index and the Brief Scale for Coping Profile, respectively. Lifestyle factors, glycated hemoglobin A1c (HbA1c) levels, and the depression statuses of the patients were also included in the analyses. Results: Among the 503 subjects with type 2 DM, 141 (28.0%) subjects exhibited probable insomnia. After adjusting for confounders, being female, living alone, and using “avoidance and suppression” were significantly correlated with current insomnia. No other relationships were found between insomnia and HbA1c or lifestyle factors, such as smoking, drinking alcohol, and exercise frequency. Conclusion: The prevalence of insomnia in individuals with type 2 DM was high, and the protective factors included some emotion-focused coping styles. Future prospective studies are required to confirm the therapeutic effects of behavioral interventions on insomnia in patients with type 2 DM. Keywords: cross-sectional studies, coping style, Japanese, insomnia, type 2 DM

Adequate vegetable intake is important in reducing the risk of lifestyle-related diseases; however, intake amongst young Japanese adults is poor. This study aimed to assess the effect of daily intake of a commercially available vegetable juice on nutritional status and metabolic syndrome-related markers in healthy young adults. Fifty-one healthy adults (14 men, 37 women), age 20 - 22 years were recruited, and their food and nutritional intake was surveyed using an FFQ based on Food Groups. Subjects were divided into either a control group, who were not administered vegetable juice, or an intervention group, who consumed 200 mL vegetable juice daily for 2 months. Anthropometric data, serum carotenoid concentrations, blood and urinary parameters were measured at baseline and at 2 months. The average intake of vegetables in all subjects at baseline was approximately 140 g/day, less than half the dose recommended by the Japanese government. Total serum carotenoid concentration in the intervention group doubled from baseline after 2 months. In particular, serum concentrations of α-carotene, β-carotene, and lycopene were increased. In the intervention group, 24-hour urinary potassium excretion increased significantly, and 24-hour urinary sodium to potassium ratio decreased significantly. Waist circumference and systolic blood pressure also decreased significantly. Daily intake of a commercial vegetable juice for 2 months improved nutritional status in young adults with inadequate vegetable intake, shown by improved serum carotenoid and urine potassium levels. In addition, intake of vegetable juice may be beneficial in reducing the risk of metabolic syndrome.

Controlling postprandial blood glucose levels can prevent and improve lifestyle-related diseases. We aimed to evaluate the effects of a commercially available vegetable juice, which is a convenient alternative to vegetables, on postprandial glucose elevation. In test 1, we confirmed the appropriate timing to consume the vegetable juice (200 mL), and demonstrated that postprandial glucose elevation was attenuated by drinking the vegetable juice with or before the experimental meal. The change in maximum concentration (ΔCmax) of blood glucose was the lowest when the vegetable juice was consumed at 30 min before the meal. In test 2, we confirmed the necessary ingestion volumes of vegetable juice (range: 68.5 - 274 mL) for attenuating the response to 50 g of carbohydrates. After drinking 200 mL of vegetable juice, the ΔCmax and incremental area under the curve values for blood glucose were significantly lower than those for after drinking the same volume of water (p < 0.05). However, a greater volume of vegetable juice did not provide an additive effect. Our results suggest that approximately 200 mL of vegetable juice at 30 min before meals is the most effective method for using vegetable juice to suppress postprandial blood glucose elevation. Stimulation of insulin secretion due to the pre-meal vegetable juice intake may contribute to this effect, although further studies are needed to identify the detailed mechanism for the attenuation.

Lycopene is the most abounding carotenoid in tomato fruits and tomato-based products, and reported to be one of the most potent singlet oxygen quencher among various dietary antioxidants. However, there are no reports on the effect of orally administered lycopene on the radical reducing ability in vivo. The radiofrequency electron paramagnetic resonance (EPR) method is a unique technique by which the in vivo reducing ability of an experimental animal can be studied. In this study, the in vivo changes in the renal reducing ability of rats orally administered lycopene were investigated using a 700 MHz EPR spectrometer equipped with a surface-coil-type resonator. Rats were fed either a control diet or a diet containing lycopene (250 mg lycopene/100 g diet) for two weeks and in vivo EPR measurements were conducted. The renal reducing ability of lycopene treated rats was significantly greater than that of the control. Although lycopene was absolutely accumulated in the kidney by lycopene supplementation, there were no notable changes in renal antioxidant enzyme activities such as superoxide dismutase and glutathione peroxidase and renal I±-tocopherol concentration between two groups. This is the first verification of in vivo antioxidant enhancement via dietary lycopene administration, although we need to clarify the mechanism of in vivo antioxidant enhancement by lycopene.

Xenobiotics are usually detoxified by drug-metabolizing enzymes and excreted from the body. The expression of many of drug-metabolizing enzymes is regulated by the aryl hydrocarbon receptor (AHR). Some substances in vegetables have the potential to be AHR ligands. To search for vegetable components that exhibit AHR-mediated transcriptional activity, we assessed the activity of vegetable extracts and identified the active compounds using the previously established stable AHR-responsive HepG2 cell line. Among the hot water extracts of vegetables, the highest activity was found in ginger. The ethyl acetate fraction of the ginger hot water extract remarkably induced AHR-mediated transcriptional activity, and the major active compound was found to be 6-shogaol. Subsequently, the mRNA levels of AHR-targeting drug-metabolizing enzymes (CYP1A1, UGT1A1, and ABCG 2) and the protein level of CYP1A1 in HepG2 cells were shown to be increased by 6-shogaol. This is the first report that 6-shogaol can regulate the expression of detoxification enzymes by AHR activation.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. It heterodimerizes with aryl hydrocarbon nuclear translocator, binds to the xenobiotic-responsive element (XRE), and enhances the transcription of genes encoding xenobiotic metabolizing enzymes. AHR also plays important roles in the inhibition of intestinal carcinogenesis and the modulation of gut immunity. It is very important to screen for AHR-activating compounds because those are expected to produce the AHR-mediated physiological functions. Until now, AHR-mediated transcriptional activity represented by the transcriptional activity of CYP1A1 in luciferase assay has been applied as a screening procedure for AHR-activating compounds. However, the AHR-mediated transcriptional activity did not necessarily correspond with the CYP1A1 transcriptional activity. To evaluate AHR-mediated transcriptional activity more specifically, and to screen for AHR-activating compounds, we establish a stable AHR-responsive HepG2 cell line by co-transfection of an AHR expression vector and an AHR-responsive vector (pGL3-XRE) containing a luciferase gene and three tandemly arranged XRE elements into a human hepatoma derived cell line, HepG2. The induction of luciferase activity in the stable AHR-responsive HepG2 cell line by typical AHR activators occurred in time- and concentration-dependent manners. By assessing the AHR target genes CYP1A1, UGT1A1, and ABCG2, an AHR activator-mediated induction was observed at mRNA level. Furthermore, the AHR activator-mediated induction of luciferase activity was positively correlated with the mRNA levels of CYP1A1, UGT1A1, and ABCG2. These findings verified the usefulness of the established stable AHR-responsive HepG2 cell line for the screening of AHR-activating compounds.

We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anti-cancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger anti-proliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.

To investigate gene(s) being regulated by ∆(9)-tetrahydrocannabinol (∆(9)-THC), we performed DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are poorly differentiated breast cancer cells, treated with ∆(9)-THC for 48 hr at an IC50 concentration of approximately 25 µM. Among the highly up-regulated genes (> 10-fold) observed, fatty acid 2-hydroxylase (FA2H) was significantly induced (17.8-fold). Although the physiological role of FA2H has not yet been fully understood, FA2H has been shown to modulate cell differentiation. The results of Oil Red O staining after ∆(9)-THC exposure showed the distribution of lipid droplets (a sign of the differentiated phenotype) in cells. Taken together, the results obtained here indicate that FA2H is a novel ∆(9)-THC-regulated gene, and that ∆(9)-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells.

There is a large demand in consumption of fly ash due to current increase of coal power plants. Fly ash in concrete as admixture contributes to decrease heat of hydration. The larger amount of fly ash is in concrete, the lower heat of hydration is generated in the early age. This is caused by substitution of fly ash for cement, which implies that less cement is mixed in the concrete. Present paper describes adiabatic temperatures of the high volume fly ash concrete. The estimated adiabatic temperature in the concrete standard specification evaluates a little higher for amounts less than 200kg/m3 of cement in concrete, and an equation of adiabatic temperature for these amounts of cement is herein proposed.

AIM: To investigate the effects of broccoli sprout extract (BSEx) on liver gene expression and acute liver injury in the rat. METHODS: First, the effects of BSEx on liver gene expression were examined. Male rats were divided into two groups. The Control group was fed the AIN-76 diet, and the BSEx group was fed the AIN-76 diet containing BSEx. After a 10-d feeding period, rats were sacrificed and their livers were used for DNA microarray and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. Next, the effects of BSEx on acute liver injury were examined. In experiments using acute liver injury models, 1000 mg/kg acetaminophen (APAP) or 350 mg/kg D-galactosamine (D-GalN) was used to induce injury. These male rats were divided into four groups: Control, BSEx, Inducer (APAP or D-GalN), and Inducer+BSEx. The feeding regimens were identical for the two analyses. Twenty-four hours following APAP administration via p.o. or D-GalN administration via i.p., rats were sacrificed to determine serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, hepatic glutathione (GSH) and thiobarbituric acid-reactive substances accumulation and glutathione-S-transferase (GST) activity. RESULTS: Microarray and real-time RT-PCR analyses revealed that BSEx upregulated the expression of genes related to detoxification and glutathione synthesis in normal rat liver. The levels of AST (70.91 ± 15.74 IU/mL vs 5614.41 ± 1997.83 IU/mL, P < 0.05) and ALT (11.78 ± 2.08 IU/mL vs 1297.71 ± 447.33 IU/mL, P < 0.05) were significantly suppressed in the APAP + BSEx group compared with the APAP group. The level of GSH (2.61 ± 0.75 nmol/g tissue vs 1.66 ± 0.59 nmol/g tissue, P < 0.05) and liver GST activity (93.19 ± 16.55 U/g tissue vs 51.90 ± 16.85 U/g tissue, P < 0.05) were significantly increased in the APAP + BSEx group compared with the APAP group. AST (4820.05 ± 3094.93 IU/mL vs 12465.63 ± 3223.97 IU/mL, P < 0.05) and ALT (1808.95 ± 1014.04 IU/mL vs 3936.46 ± 777.52 IU/mL, P < 0.05) levels were significantly suppressed in the D-GalN + BSEx group compared with the D-GalN group, but the levels of AST and ALT in the D-GalN + BSEx group were higher than those in the APAP + BSEx group. The level of GST activity was significantly increased in the D-GalN + BSEx group compared with the D-GalN group (98.04 ± 15.75 U/g tissue vs 53.15 ± 8.14 U/g tissue, P < 0.05). CONCLUSION: We demonstrated that BSEx protected the liver from various types of xenobiotic substances through induction of detoxification enzymes and glutathione synthesis.

Δ9-Tetrahydrocannabinol (Δ9-THC) has been reported as possessing antiestrogenic activity, although the mechanisms underlying these effects are poorly delineated. In this study, we used the estrogen receptor α (ERα)-positive human breast cancer cell line, MCF-7, as an experimental model and showed that Δ9-THC exposures markedly suppresses 17β-estradiol (E2)- induced MCF-7 cell proliferation. We demonstrate that these effects result from Δ9-THC’s ability to inhibit E2-liganded ERα activation. Mechanistically, the data obtained from biochemical analyses revealed that (i) Δ9-THC up-regulates ERβ, a repressor of ERα, inhibiting the expression of E2/ERα-regulated genes that promote cell growth and that (ii) Δ9-THC induction of ERβ modulates E2/ERα signaling in the absence of direct interaction with the E2 ligand binding site. Therefore, the data presented support the concept that Δ9-THC’s antiestrogenic activities are mediated by the ERβ disruption of E2/ERα signaling. INTRODUCTION Δ9-Tetrahydrocannabinol (Δ9-THC), a major component of marijuana, exhibits a variety of pharmacological and toxicological effects.1–4 Among Δ9-THC’s biological activities, its recognized antiestrogenic activity has been the subject of several investigations. An early hypothesis suggested that Δ9-THC may bind directly to the estrogen receptor α (ERα), thus interfering with 17β-estradiol (E2) ligand binding. However, this mode of action now appears unlikely, and the molecular mechanism(s) of Δ9-THC-mediated antiestrogenic effects are still under debate.5,6 Since Δ9-THC is used both recreationally and medicinally for the treatment of pain and nausea in cancer patients undergoing chemotherapy in the United States and other countries (i.e., medical marijuana), it is important to ascertain the mechanistic basis of Δ9-THC’s E2 signaling disruption. The proliferation of the ERα-positive breast cancer MCF-7 cell line is stimulated by E2, resulting from the activation of E2/ERα signal transduction pathways. In 1996, Kuiper et al. identified a second ER, ERβ.7 In contrast to ERα, the physiological role of ERβ is not fully understood, although ERβ is recognized as a repressor of ERα’s activity, both through its ability to heterodimerize with the α isoform and its direct function as a ERβ/β homodimer.7–12 In addition, it has been suggested that ERβ may act as a tumor suppressor and that the loss of ERβ promotes breast carcinogenesis.9,13 Although Δ9-THC effects have been studied in the MCF-7 cell model, to the best of our knowledge no mechanistic data are available to account for Δ9-THC’s antiestrogenic action. Here, we report that Δ9-THC disrupts E2/ERα signaling in MCF-7 cells through up-regulation of ERβ expression, resulting in altered proliferative responses, and that these effects occur in the absence of direct interaction of Δ9-THC with ERβ’s ligand binding site.

To investigate gene(s) being regulated by ∆(9)-tetrahydrocannabinol (∆(9)-THC), we performed DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are poorly differentiated breast cancer cells, treated with ∆(9)-THC for 48 hr at an IC50 concentration of approximately 25 µM. Among the highly up-regulated genes (10-fold) observed, fatty acid 2-hydroxylase (FA2H) was significantly induced (17.8-fold). Although the physiological role of FA2H has not yet been fully understood, FA2H has been shown to modulate cell differentiation. The results of Oil Red O staining after ∆(9)-THC exposure showed the distribution of lipid droplets (a sign of the differentiated phenotype) in cells. Taken together, the results obtained here indicate that FA2H is a novel ∆(9)-THC-regulated gene, and that ∆(9)-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells.

Cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, has been reported to possess diverse biological activities, including anti-proliferative effect on cancer cells. Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), few studies have investigated whether CBDA itself is biologically active. Results of the current investigation revealed that CBDA inhibits migration of the highly invasive MDA-MB-231 human breast cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA. It is established that activation of the RhoA signaling pathway leads to inhibition of the mobility of various cancer cells, including MDA-MB-231 cells. The data presented in this report suggest for the first time that as an active component in the cannabis plant, CBDA offers potential therapeutic modality in the abrogation of cancer cell migration, including aggressive breast cancers.

Although it has been reported that dietary lycopene, the main carotenoid in tomato, improved drug-induced nephropathy, there are no reports on the effect of orally administered lycopene on the in vivo renal reducing (i.e., antioxidant) ability. The radiofrequency electron paramagnetic resonance (EPR) method is a unique technique by which the in vivo reducing ability of an experimental animal can be studied. In this study, the in vivo changes in the renal reducing ability of rats orally administered lycopene were investigated using a 700 MHz EPR spectrometer equipped with a surface-coil-type resonator. Rats were fed either a control diet or a diet containing lycopene. After 2 weeks, in vivo EPR measurements were conducted. The renal reducing ability of lycopene-treated rats was significantly greater than that of the control. This is the first verification of in vivo antioxidant enhancement via dietary lycopene administration.

Alpha-lipoic acid (LA) is used in dietary supplements or food with antioxidative functions. The mechanism for the intestinal absorption of alpha-lipoic acid was investigated in this study by using human intestinal Caco-2 cell monolayers. LA was rapidly transported across the Caco-2 cell monolayers, this transport being energy-dependent, suggesting transporter-mediated transport to be the mechanism involved. The LA transport was strongly dependent on the pH value, being accelerated in the acidic pH range. Furthermore, such monocarboxylic acids as benzoic acid and medium-chain fatty acids significantly inhibited LA transport, suggesting that a proton-linked monocarboxylic acid transporter (MCT) was involved in the intestinal transport of LA. The conversion of LA to the more antioxidative dihydrolipoic acid was also apparent during the transport process.