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Silibinin, a major component of milk thistle extract silymarin, promotes hypoglycemia by activating estrogen receptor (ER) α and β-mediated pathways in pancreatic β-cells. Glucagon-like peptide-1 (GLP-1) is the enteroendocrine peptide produced in L-cells, and it controls glucose homeostasis through multiple pathways. The effect of silibinin on L-cell mass and function is still unknown.The protective effect of silibinin on palmitate (PA)-treated intestinal L-cell line GLUTag cells and the SHRSP•Z-Leprfa/Izm-Dmcr (SP•ZF) diabetic rat model was investigated in current study.After pre-incubation with 50 μM silibinin for 4 h, GLUTag cells were treated with 0.125 mM PA. MTT, Annexin V/PI apoptosis, Hoechst 33342 staining, western blot, DCFH-DA, GLP-1 ELISA, qRT-PCR and immunofluorescence analyses were undertaken to determine ER-dependent protection of silibinin against PA-induced cellular damage. The differential protein expression of GLUTag cells under different treatments was examined by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). The SP•ZF diabetic rat model was chosen for in vivo study. After 4 weeks of gastric gavage with 100 or 300 mg kgThe current study showed that the GLUTag cells preincubated with silibinin activated the transcription factor nuclear erythroid-2 like factor-2 (Nrf2)-antioxidant pathway, reduced reactive oxygen species (ROS) generation, and improved cell survival and GLP-1 content, while the antioxidative effect of silibinin was blocked by the selective ERα antagonist MPP or ERβ antagonist PHTPP in GLUTag cells. Our proteomics data further revealed that ERα or β inactivation reduced glutathione peroxide and proteins associated with endocytosis and reproduction, thus at least partially reversing the protective effect of silibinin. SP•ZF rats received silibinin treatment showed increased serum GLP-1 content and improved glucose homeostasis. Furthermore, silibinin upregulated ERα and β levels and reduced the level of 8-OHdG in GLP-1-positive cells.Our study showed that silibinin improved L-cell mass and function through an ER-mediated antioxidant pathway, and the proteomics analysis revealed for the first time the differential regulation of proteins by PA and silibinin in GLUTag cells.

Geriatric surgery poses specific challenges due to patient vulnerability in relation to aging. We analyzed perioperative challenges concerning super-elderly patients with breast cancer. Between 2013 and 2018, 908 patients with breast cancer were treated surgically. Of these, two patient groups were compared: Group A (≥ 85 years old, n = 34, 3.7%) and Group B (75–84 years old, n = 136, 15%). In Groups A and B, 26.4% and 36.8% of patients lived alone, respectively. Group A patients had higher rates of psychiatric and cardiovascular disease (32.4% and 41.2%) than Group B (8.8% and 16.2%) (p = 0.0009 and p = 0.0031, respectively). There was no marked difference in the type of surgery or length of hospital stay between groups, and most complications involved surgical site disorders. Postoperatively, Group A had a higher rate of delirium (29.4%) than Group B (3.7%) (p

Aim This study was conducted in order to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus trastuzumab followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) in a neoadjuvant chemotherapy (NAC) setting for patients with human epidermal growth factor receptor 2 (HER2)-positive operable breast cancer. Patients and methods Each patient received four cycles of 260 mg/m2 nab-paclitaxel with 6 mg/kg trastuzumab (8 mg/kg as the loading dose) every 3 weeks (q3w) followed by four cycles of FEC (500/100/500 mg/m2) q3w. The primary endpoint was pathological complete response (pCR) rate. Results Twenty-nine patients were analyzed for the efficacy and safety of this treatment. All patients completed four cycles of nab-paclitaxel and trastuzumab, and 28 patients completed four cycles of FEC. Twenty-seven patients subsequently underwent surgery. The pCR rate was 74.0%. The most frequent toxicity was sensory neuropathy (96.6%), but grade 3 neuropathy rate was 3.4%. Conclusion Nab-paclitaxel plus trastuzumab followed by FEC in patients with HER2-positive operable breast cancer is considerably effective and well tolerated.

Physical activity refers to any body movement that increases energy expenditure, such as walking, running, cycling, staircase climbing, and recreational activities. On the other hand, a sedentary l...

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life.

To evaluate whether endothelial dysfunction and hypertension are prevented by trans-cinnamaldehyde (tCA) through the activation of endothelial nitric oxide synthase (eNOS).Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and stimulated with tCA to determine cell viability using the methyl thiazolyl tetrazolium assay. The effect of tCA on nitric oxide (NO) production was determined by diaminofluorescein-dyes in the absence or presence of inhibitors of eNOS, AMPK, PKA, and AKT. The effect of tCA on blood pressure was determined by the tail-cuff method in obesity spontaneous hypertension (SHR. Cg-Leprcp/NDmcr) rats. The phosphorylation of eNOS and protein expression of the insulin-signaling pathway (InsR-IRS1-PI3K-AKT) were measured by western blot.tCA at concentrations less than 100 ¦ÌM did not affect cell viability in cultured HUVECs. Stimulation with tCA promoted NO release in a time-dependent manner compared with the control group. tCA-treated HUVECs also significantly increased AKT-Ser473 and eNOS- Ser1177 phosphorylation. In SHR-CP rats, treatment with tCA at a dose of 40 mg/kg/day for 6 weeks markedly reduced the systolic blood pressure and diastolic blood pressure, increased the phosphorylation of AKT and eNOS, and increased urinary nitric oxidation.tCA attenuated endothelial dysfunction and reduced blood pressure in SHR-CP rats. The underlying mechanisms may involve the increase in AKT and eNOS phosphorylation and the release of eNOS-derived NO.

A 74-year-old woman presented with epigastric pain. Imaging revealed a tumor measuring 80 mm, with internal necrosis, originating from the gallbladder and invading the liver. We performed extended anterior segmentectomy of the liver and lymph node resection following a preoperative diagnosis of gallbladder cancer. Histologically, the tumor was diagnosed as an undifferentiated carcinoma of the gallbladder. Although curative resection was performed, the patient developed recurrence with liver metastasis and peritoneal dissemination after 6 postoperative weeks and died after 10 postoperative weeks.

In June 2018, a 75-year-old woman was admitted for right upper quadrant pain. She had a history of radical mastectomy for left breast cancer in April 2009. The axillary lymph node, bone, gastric, and pleural metastases had been treated with hormonal therapy for 2 years from April 2016. Based on the examination findings, we diagnosed her with acute calculous cholecystitis and performed emergency percutaneous transhepatic gallbladder drainage(PTGBD). Eleven days after PTGBD, we performed laparoscopic cholecystectomy. Pathological examination revealed a metastatic tumor from breast cancer in her gallbladder. Although her postoperative course was uneventful, the patient died of progression of the other organ metastasis 7 months after cholecystectomy. Gallbladder metastasis should be considered in patients with advanced breast cancer who present symptoms of cholecystitis.

Silibinin, a flavonolignan derived from milk thistle (Silybum marianum), has been revealed to have a beneficial effect on improving diabetes-impaired glycemic control. However, the underlying mechanism is still unclear. In the present study, to evaluate whether the gut-brain-liver axis, an important neural pathway for the control of hepatic glucose production, is involved in silibinin-regulated glucose homeostasis, the expression of glucagon-like peptide-1 receptor (GLP1R) in the duodenum, activation of neurons in the nucleus of the solitary tract (NTS), as well as glycogen accumulation and expression of gluconeogenic enzymes in the livers of diabetic SHRSP·Z-Leprfa/IzmDmcr (SP·ZF) rats with 4-week oral administration of silibinin (100 and 300 mg kg-1 day-1) were evaluated. Common hepatic branch vagotomy was further conducted in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic SD rats to confirm the role of the gut-brain-liver axis in silibinin-improved glycemic control. The results revealed a significant inhibition of fasting blood glucose after SP·ZF rats were administrated with silibinin for 4 weeks. The expression of GLP1R in the duodenum and the activation of neurons in the NTS increased, while hepatic glucose production decreased on silibinin administration. However, the hypoglycemic effect of silibinin was reversed by common hepatic branch vagotomy in diabetic SD rats. Our study suggested that silibinin may be useful as a potential functional food ingredient against diabetes by triggering the gut-brain-liver axis.

Coronavirus Disease-2019 (COVID-19), an infectious disease associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global emergency with high mortality. There are few effective treatments, and many severe patients are treated in an intensive care unit (ICU). The purpose of this study was to evaluate whether the Japanese Kampo medicine ninjin'yoeito (NYT) is effective in treating ICU patients with COVID-19. Nine patients with confirmed SARS-CoV-2 infection admitted to the ICU were enrolled in this study. All patients underwent respiratory management with invasive mechanical ventilation (IMV) and enteral nutrition. Four patients received NYT (7.5 g daily) from an elemental diet tube. We retrospectively examined the prognostic nutritional index (PNI), length of IMV, length of ICU stay, length of hospital stay, rate of tracheostomy, and mortality rate. The median age of the enrolled participants was 60.0 years (4 men and 5 women). The median body mass index was 27.6. The most common comorbidity was diabetes (4 patients, 44%), followed by hypertension (3 patients, 33%) and chronic kidney disease (2 patients, 22%). The median length of IMV, ICU stay, and hospital stay were all shorter in the NYT group than in the non-NYT group (IMV; 4.0 days vs 14.3 days, ICU; 5.3 days vs 14.5 days, hospital stay; 19.9 days vs 28.2 days). In the NYT and non-NYT groups, the median PNI at admission was 29.0 and 31.2, respectively. One week after admission, the PNI was 30.7 in the NYT group and 24.4 in non-NYT group. PNI was significantly (p = 0.032) increased in the NYT group (+13.6%) than in the non-NYT group (-22.0%). The Japanese Kampo medicine NYT might be useful for treating patients with severe COVID-19 in ICU. This study was conducted in a small number of cases, and further large clinical trials are necessary.

// Shuang Ling 1, * , Rong-Zhen Ni 1, 2, * , Yunyun Yuan 1 , Yan-Qi Dang 1 , Qian-Mei Zhou 1 , Shuang Liang 2 , Fujiang Guo 3 , Wei Feng 4 , Yuanyuan Chen 1 , Katsumi Ikeda 5 , Yukio Yamori 6 and Jin-Wen Xu 1 1 Institute of Interdisciplinary Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China 2 Engineering Research Center of Modern Preparation Technology of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China 3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China 4 School of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China 5 School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan 6 Institute for World Health Development, Mukogawa Women's University, Nishinomiya, Japan * These authors have contributed equally to the work Correspondence to: Jin-Wen Xu, email: jinwen.xu88@gmail.com Keywords: endothelial progenitor cell, bavachlcone, neovascularization, RORα, erythropoietin Received: June 14, 2017 Accepted: August 06, 2017 Published: September 16, 2017 ABSTRACT In cardiovascular diseases, endothelial function is impaired and the level of circulating endothelial progenitor cells (EPCs) is low. This study investigated whether the natural bioactive component bavachalcone (BavaC) induces the differentiation of EPCs and neovascularization in vivo ; the underlying mechanisms were also examined. We observed that the treatment of rat bone marrow–derived cells with a very low dose of BavaC significantly promoted EPC differentiation. In our hindlimb ischemia models, low–dose BavaC administered orally for 14 days stimulated the recovery of ischemic hindlimb blood flow, increased circulating EPCs, and promoted capillary angiogenesis. The BavaC treatment of rat bone marrow cells for 24 h initiated the AMP–activated protein kinase (AMPK) activity required for the differentiation of EPCs. Further testing revealed that BavaC and CGP52608, a retinoic acid receptor–related orphan receptor α (RORα) activator, enhanced the activity of RORα1 and EPO luciferase reporter gene. BavaC treatment also elevated EPO mRNA and protein expression in vitro and in vivo and the circulating EPO levels in rats. By contrast, the RORα antagonist VPR66 inhibited BavaC–induced EPO reporter activity, and differentiation of bone marrow cells into endothelial progenitor cells. Overall, this study revealed that BavaC promotes EPC differentiation and neovascularization through a RORα–EPO–AMPK axis. BavaC can be used as a promising angiogenesis agent for enhancing angiogenesis and tissue repair.

Sentinel node biopsy (SNB) after neoadjuvant therapy (NAT) for breast cancer remains controversial. We conducted a retrospective study of patients who underwent SNB after NAT to evaluate the effectiveness of this procedure. A consecutive 105 women with locally advanced breast cancer (cT1–4, cN0–3, M0) were treated with NAT between 2006 and 2015. The subjects were 80 of these patients who became or remained clinically node-negative after NAT, 53 of whom had axillary management determined by SNB (group A) and the other 27 underwent axillary lymph node dissection (ALND) without SNB (group B). SNB was performed using a modified dye method. The sentinel node (SN) identification rate was 94.3% and the mean number of removed SNs was 2.4. ALND was avoided in 33 patients, who were confirmed as SN-negative. There was no difference in recurrence-free and overall survival rates between groups A and B (p = 0.71 and p = 0.46, respectively) during the median follow-up time of 63 months. Of the 33 patients who did not undergo ALND, 10 suffered recurrence (33%). One patient (3%) had recurrence in an axillary lymph node and four had recurrence in a supraclavicular lymph node. Axillary SNB after NAT did not affect the axillary failure rate or the prognosis. SNB may be a reliable procedure, even after NAT.

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted.

There are many studies on eye and mouse movement. However, there are not many studies that try to evaluate the skill of Web search while considering the relationship between the line of sight and the movement of the mouse. In this study, we analyze the data acquired from the viewpoint of the differences in information literacy of subjects and investigate the method of quantitatively evaluating the skill of web search.

Conventionally, it has been pointed out that the eye movement when using the PC correlates with the movement of the mouse, and those are utilized as additional information on the usability improvement and other observed data. This study had analized the eye movement and the mouse movement data, and had examined the method to estimate the user’s skill.

“Hanshin Park” located in Nishinomiya, Hyogo prefecture was an amusement park owned and operated by the Hanshin electric railway company limited. The park was opened near Koshien Stadium in 1929, using the land after the exposition of accession for Emperor Showa. In the1930’s it had a chimpanzee, extremely unusual to see for the public in Japan. Unfortunately, the park was closed in 2003. We investigated the history of the facility the chimpanzees lived in, by checking documents, newspaper articles, and research papers. The female chimpanzee named“ Opera” was imported to Japan from Africa in 1934 and she became nationally famous, riding a bicycle, walking on stilts, and so on. Although it is not known when Opera died, it is estimated that she lived there for 2 to 5 years. A male chimpanzee named“ Bamboo” came to Kobe around 1940. Because the site of the park was using for military airport, he had to move to Higashiyama Zoo, Nagoya-city in 1943. By the end of World War II, he was the only chimpanzee still alive in Japan. Hanshin Park was opened again nearby in 1950 and a female chimpanzee named“ Birdie” arrived in 1973. Two of the three chimpanzees found in this research were not registered in the Japanese Association of Zoos and Aquariums studbook. The information will be valuable not only for learning more about captive chimpanzees but also for improvement of their welfare.

Background/aim In our previous study, first-line eribulin (ERI) showed 25 weeks of progression-free survival (PFS). This study investigated the efficacy and safety of ERI re-administration in metastatic breast cancer (MBC) patients. Patients and methods HER2-negative MBC patients who had never received chemotherapy for MBC received first-line ERI for 18 weeks if they did not have disease progression, and then one cycle of S-1 before ERI re-administration. Results Twelve patients received ERI re-administration. The PFS of re-administered ERI was 13 weeks. Total duration of ERI use was 30 weeks. The incidence and severity of adverse events were consistent with previous reports. Conclusion In the first-line setting, the total PFS of eribulin was extended by S-1 administration before disease progression, compared with that of our previous report.

Angelica acutiloba Kitagawa (Yamato Toki) is a herbal medicine known to exhibit various health effects. In this study, we used a rat model to examine the effects of two different Yamato Toki extracts on the blood flow response of the instep of the hind paw. Twelve-week- old male stroke-prone spontaneously hypertensive rats (SHRSP) were orally given 200 mg of a water extract of Yamato Toki (n=6), 200 mg of an ethanol extract of Yamato Toki (n = 6), 30 mg/kg of nicardipine (n = 6) as a positive control and saline (n = 6) as a negative control. Blood flow was monitored continuously for 0, 1, 3, 6 and 24 hours after treatment. Rats given 200 mg of the ethanol extract of Yamato Toki demonstrated significantly greater blood flow compared with control rats at I hour after treatment. An ethanol extract of Yamato Toki from Nara administrated orally can increase blood flow in SHRSP.

Background/aim Nab-paclitaxel (nab-PTX) is an albumin-bound paclitaxel formulation. Although nab-PTX has shown superior efficacy compared to conventional paclitaxel (PTX) in metastatic breast cancer (MBC), chemotherapy-induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In this study, we aimed to estimate the feasibility of the nab-PTX 175 mg/m2/3weeks regimen. Patients and methods Patients having metastatic or inoperable HER2-negative breast cancer received 175 mg/m2 of nab-PTX every three weeks. The primary endpoint was safety and the secondary endpoints were response and survival. Results Seventeen patients were enrolled with a median age of 64 years. Ten patients had estrogen receptor positive disease and seven had triple-negative disease. CIPN was observed in seven patients (41%) however, grade 3 CIPN was only seen in one patient (6%). Objective response rate was 41% and progression-free survival was 23 weeks. Conclusion Nab-PTX 175 mg/m2/3wks regimen has a good safety profile and less frequent CIPN. This regimen can contribute to the strategy of MBC treatment.

Objective 3,4-Oxo-isopropylidene-shikimic acid (ISA), a derivative of shikimic acid, has exhibited ameliorative effect on cognitive impairment in experimental animal models of dementia. This study investigated the effect of ISA on lipid accumulation and adipokine secretion during differentiation of 3T3-L1 fibroblasts to adipocytes. Methods 3T3-L1 cells were cultured and treated with ISA (50–800 μM) from days 3–8. Lipid accumulation and triglyceride content were measured. Gene expression of adipokines (adiponectin, leptin, and resistin), CCAAT/enhancer binding protein (C/EBP) β, C/EBP α and peroxisome proliferator-activated receptor γ (PPAR γ) and PPAR target genes, including adipocyte fatty acid binding protein (aP2) and fatty acid synthase (FAS) were investigated. Results ISA promoted 3T3-L1 fibroblast differentiation to adipocytes and increased triglyceride content by 26%. On mechanistic levels, ISA increased expressions of C/EBP β, PPAR γ, C/EBP α, aP2 and FAS. Moreover, ISA stimulated expressions of adipokines secreted by adipocytes, including adiponectin, leptin, and resistin. Conclusions These findings demonstrated that ISA promoted adipogenesis by up-regulating expressions of C/EBP β, PPAR γ, C/EBP α, aP2 and FAS, and also stimulated adipokines during adipocyte differentiation. Further study should clarify the relationship between stimulation of adipokines and cognitive enhancing effect of ISA.

Background: The cranial collector (CC) is known as a direct drainage lymphatic duct from the extremities to the axilla and running near the axillary vein. It might be helpful in avoiding incidence of lymphedema (LE) in patients with axillary lymph node dissection (ALND). However, it is not clear how the CC may influence for the incidence of LE after ALND and adjuvant treatments. Methods: A study was performed from December 2009 to April 2018 in 217 patients with breast cancer who underwent ALND with axillary reverse mapping (ARM). The ARM was performed by fluorescence imaging following the injection of indocyanine green into the ipsilateral arm. In 208 of the 217 patients, we investigated the relationship between the CC status identified by ARM and the incidence of LE in patients administered adjuvant treatments. Results: We identified the CC in the axilla of 81 of the 208 patients. The CC-negative patients had a significantly greater incidence of LE than that in CC-positive patients (P=0.0007, hazard ratio: 2.54). Among 127 CC-negative patients, younger age and adjuvant chemotherapy (mostly anthracycline and/or taxanes) were significant risk factors for LE. In contrast, radiation, especially that with supraclavicular radiation (SCRT) was a significant risk factor for LE in CC-positive patients. Conclusions: The CC status of patients undergoing ALND might affect the incidence of LE after the adjuvant chemotherapy or radiation.

We observed changes in body weight and fat tissue organs in SHRSP・Z-Leprfa/NDmcr（SPZF） rats at 12 and 18 weeks of age. Plasma glucose and insulin concentrations were significantly higher in SPZF than in WKY rats. Homeostasis model assessment-insulin resistance in SPZF was significantly higher than in WKY rats. MG53 protein expression in skeletal muscles from SPZF was significantly higher than that in skeletal muscles from WKY rats. These findings suggest that SPZF shows insulin resistance. MG53 may affect the development of insulin resistance in SPZF.

The generation of oxidative stress, characterized by enhanced reactive oxygen species (ROS) formation, has been found in obesity. ROS production was increased during the differentiation of 3T3-L1 cells into adipocytes. We previously reported that caffeic acid phenethyl ester (CAPE) suppresses 3T3-L1 differentiation to adipocytes through the inhibition of peroxisome proliferator-activated receptor γ. In this study, the preventive effect of CAPE on oxidative stress in 3T3-L1 cells was observed. The results were as follows: (1) ROS production during 3T3-L1 cell differentiation to adipocytes was significantly (p0.05) suppressed by CAPE treatment in a concentration-dependent manner, (2) with CAPE treatment, the extracellular superoxide dismutase mRNA expression level significantly increased, but the NOX4 mRNA expression level did not change, and (3) CAPE treatment significantly increased superoxide dismutase (SOD) activity in 3T3-L1 cells. From these results, we suggest that the increased oxidative stress in 3T3-L1 differentiation to adipocytes is attenuated by CAPE treatment. This attenuation may be partly caused by increased SOD production.

The circadian variations in the hemodynamics and locomotor activity (ACT) of congenic rats derived from stroke-prone spontaneously hypertensive (SHRSP) rats and Wistar-Kyoto (WKY) rats have not been studied in detail. We used radio telemetry and the maximum entropy method to examine these variations. The systolic arterial pressure of the congenic rats was intermediate between those of the SHRSP rats and WKY rats, while their heart rate was lower than that of the SHRSP rats. The congenic rats also showed the highest ACT. The circadian variations in the heart rates of the congenic rats were more like those of the WKY rats, and the variations in their ACT were more similar to those of the SHRSP rats.

Amla (Emblica officinalis Gaertn.) is a rich dietary source of vitamin C, minerals and amino acids, and also contains a wide variety of phenolic compounds. Amla has also been used as a principal constituent of many preparations of Ayurved, the Indian system of traditional medicine. Gelatin hydrolysate, also known as collagen peptide as a functional ingredient, is obtained from animal hide or fish scales. Ingestion of gelatin or collagen peptide affects various functions of the body, including bone, the achilles tendon, and skin. However, there are few data on the effects of amla extract and collagen peptide on photoaging in vivo. In the present study, therefore, we administered amla extract and/or collagen peptide to hairless mice that were repeatedly exposed of UVB irradiation, and examined the resulting effects on photoaging. Amla extract and collagen peptide suppressed the formation of 8-OHdG-positive cells and epidermal hyperplasia, and controlled skin hydration, thus reducing skin wrinkle formation in the mice. Collagen peptide, but not amla extract, also enhanced the production of collagen. We demonstrated that amla extract and collagen peptide exerted an additive effect in ameliorating skin dehydration and wrinkle formation, suggesting that they were able to attenuate photoaging effectively in UVB-irradiated hairless mice.

The treatment goals for metastatic breast cancer (MBC) are prolonging survival and improving the quality of life. Eribulin, a non-taxane tubulin inhibitor, demonstrated improved survival in previous studies and also showed mild toxicity when used in late-line therapy for MBC. We conducted a phase II study to investigate the efficacy of eribulin mesylate as the first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative MBC. This was a phase II, open-label, single-arm, multicenter trial conducted in Japan. Patients with HER2-negative MBC received intravenous eribulin (1.4 mg/m(2) on days 1 and 8 of each 21-day cycle). The primary efficacy outcome was overall response rate (ORR). Secondary outcomes included time to treatment failure, progression-free survival (PFS), overall survival (OS), and safety. A total of 35 patients were enrolled and received a median of 8 (range 1-21) cycles of eribulin therapy. ORR and clinical benefit rate were 54.3 and 62.9 %, respectively. Median PFS was 5.8 months and median OS was 35.9 months. Grade 3 or 4 neutropenia was observed in 63 % of patients. The majority of non-hematological adverse events were mild in severity. The present trial demonstrated that eribulin has antitumor activity comparable with other key established cytotoxic agents with acceptable safety and tolerability. Thus, eribulin as first-line chemotherapy might be beneficial for patients with HER2-negative MBC.

The aim of this study was to identify the molecular mechanisms underlying high-fat and high-cholesterol (HFC) diet-induced steatohepatitis and associated liver fibrosis progression in a novel stroke-prone, spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rat model.SHRSP5/Dmcr rats were given the control or HFC-diet for 2, 8, and 16 weeks. Plasma and hepatic gene expression of key molecules involved in fatty acid oxidation, inflammation, oxidative stress, and fibrosis were subsequently analyzed.Rats fed the HFC-diet showed increased plasma tumor necrosis factor-α (TNF-α) and hepatic p50/p65 signals, but reduced hepatic Cu(2+)/Zn(2+)-superoxide dismutase across the treatment period and reduced plasma total adiponectin at 8 weeks. In HFC-diet-fed rats, transforming growth factor-β1 (TGF-β1) was elevated prior to the appearance of obvious liver fibrosis pathology at 2 weeks, followed by elevations in platelet-derived growth factor-B (PDGF-B) and α-smooth muscle actin (α-SMA), corresponding to evident liver fibrosis, at 8 weeks and by α(1) type I collagen production at 16 weeks. The HFC-diet increased hepatic total cholesterol accumulation, although hepatic triglyceride declined by 0.3-fold from 2 to 16 weeks due to reduced hepatic triglyceride synthesis, as suggested by the diacylglycerol acyltransferase 1 and 2 measurements.TNF-α and p50/p65 molecular signals appeared to be major factors for HFC-diet-induced hepatic inflammation and oxidative stress facilitating liver disease progression. While the up-regulation of TGF-β1 prior to the appearance of any evident liver fibrosis could be an early signal for progressive liver fibrosis, elevated PDGF-B and α-SMA levels signified evident liver fibrosis at 8 weeks, and subsequent increased α(1) type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.

Angiogenesis is a promising target for cancer prevention and treatment. This study aimed to determine the antiangiogenic effects of melinjo (Gnetum gnemon L.) seed extract and its resveratrol derivative components, such as gnetin C (GC), gnetin L (GL), gnemonoside A (GMA), gnemonoside C (GMC), and gnemonoside D (GMD). An ethanol extract of melinjo seeds (EEMS) and the two gnetins markedly inhibited the proliferation and tube formation of human umbilical vein endothelial cells (HUVEC) stimulated with vascular endothelial growth factor and basic fibroblast growth factor. The inhibitory effects of GC and GL were much stronger than those of resveratrol. GMC and GMD inhibited only proliferation, whereas GMA had almost no effect on the two endothelial cell functions. The EEMS and GC also reduced the cell viability of tube-forming HUVEC, with accompanying ERK1/2 inactivation, and suppressed the migration of HUVEC. Furthermore, dietary intake of EEMS significantly inhibited tumor angiogenesis in a mouse dorsal air sac assay. In conclusion, we found that the EEMS and its resveratrol derivatives, particularly GC, suppress multiple angiogenesis-related endothelial cell functions and/or tumor angiogenesis, indicating that the melinjo seeds and the natural resveratrol derivatives may be useful for cancer prevention and treatment.

Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today. This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease. Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and high-cholesterol-containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14 weeks. The HFC diet significantly increased serum transaminase and gamma glutamyl transpeptidase activities, tumor necrosis factor alpha levels, and serum and hepatic total cholesterol levels over time. In contrast, this diet decreased serum albumin, glucose, and adiponectin levels throughout or the later stage of the feeding period, but did not influence serum insulin levels. Histopathologically, the HFC diet increased microvesicular steatosis, and focal or spotty necrosis with lymphocyte infiltrations were observed in the liver at 2 weeks, macrovesicular steatosis, ballooned hepatocytes with Mallory-Denk body formation in some, and multilobular necrosis and fibrosis at 8 weeks. Interestingly, this fibrosis formed a honeycomb network at 14 weeks. These changes are very similar to those observed in patients with non-alcoholic steatohepatitis. SHRSP5/Dmcr rats appear to be a useful model for analyzing the time-dependent changes of HFC diet-induced steatohepatitis and fibrosis progression.

Background The role of elastography for breast tumors is still ambiguous. The purpose of this study was to inquire how effectively elastography can be used in the diagnosis of breast tumors.

We previously reported that caffeic acid phenethyl ester (CAPE) suppresses 3T3-L1 differentiation to adipocytes through the inhibition of peroxisome proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, fatty acid synthase (Fas) and adipocytes-specific fatty acid binding protein 2 (aP2) expressions (Juman et al., Biol. Pharm. Bull., 33, 1484-1488 (2010)). In the present study, we confirmed that CAPE had inhibitory effects on increased glycerol-3-phosphate dehydrogenase (GPDH) activity and an increased insulin receptor substrate 1 (IRS-1). Our data show that treatment with 50 µM CAPE significantly reduced the levels of leptin (p

Flax oil feeding has been proposed to have beneficial effects on the outcome of the metabolic syndrome due to the highn-3 fatty acid content of flax oil; however, the mechanisms of its action remain largely unknown. We investigated the effects of flax oil feeding on hyperlipidaemia, hyperglycaemia, hepatic steatosis and oxidative stress in the spontaneously hypertensive (SHR)/NDmcr-cp rats, a genetic model of the metabolic syndrome. Hepatic gene expression of PPAR-α, PPAR-γ and sterol-regulatory element-binding protein-1c was also assessed in order to investigate the possible underlying mechanisms. Obese and lean SHR/NDmcr-cp rats were fed high-fat diets enriched with either lard or flax oil for a period of 4 weeks. Obese rats exhibited higher body weight, liver weight and mesenteric fat-, epididymal fat- and renal fat-pad weights, and also TAG and cholesterol concentrations in serum and VLDL, LDL and HDL fractions, when compared with the lean rats (P P P r− 0·98,P

We investigated the inhibitory effect of caffeic acid phenethyl ester (CAPE) on the differentiation of 3T3-L1 mouse fibroblasts to adipocytes. 3T3-L1 cells were differentiated for adipocytes given high glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 1 microM dexamethasone (DEX), 500 microM isobutylmethylxanthine (IBMX), and 5 microg/ml insulin for 7 days. After differentiation, cells were stained with Oil-Red-O to detect oil droplets in adipocytes. Additionally, the cells were lysed and measured for triglyceride contents. Total RNA was isolated from differentiated cells on day 0, 4 and 7. Then, RNA was analyzed using reverse transcription (RT)-polymerase chain reaction (PCR). CAPE dose-dependently suppressed oil droplet accumulation and reduced the droplet size. These findings showed that CAPE at concentrations of 25 to 50 microM could significantly inhibit triglyceride deposition (p0.05). Treatment of 3T3-L1 with CAPE reduced the mRNA levels of peroxisome proliferator-activated receptor (PPAR) gamma and CCAAT/enhancer-binding protein (C/EBPalpha). Fatty acid synthase (Fas) and adipocyte-specific fatty acid binding protein (aP2) are known to be associated with lipid metabolism in adipocytes, and both Fas mRNA and aP2 mRNA were significantly suppressed by CAPE treatment. These findings suggested that CAPE suppresses 3T3-L1 differentiation to adipocytes through inhibition of PPARgamma, C/EBPalpha, Fas and aP2 expression.

Genistein, an isoflavone, was shown to have therapeutic effects for obesity, diabetes and cardiovascular diseases. This study investigated the effect and underlying mechanism of genistein on adipogenesis in 3T3-L1 preadipocytes. Genistein inhibited lipid accumulation and decreased the nonesterified fatty acid (NEFA) content of 3T3-L1 on day 6 after the induction of differentiation with methylisobutylxanthine, dexamethasone and insulin (MDI). Genistein recovered nitric oxide (NO) release suppressed by MDI and the results were consistent with the expression of endothelial NO synthase (eNOS) assayed by western blotting. Pretreatment with genistein inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) stimulated with 10 microg/mL of insulin. Furthermore, genistein inhibited the expression of fatty acid synthase (FAS) from 178% of the MDI group to 74%. SB203580, a p38 inhibitor, mimicked the FAS inhibition effect of genistein, suggesting that the inhibitory effect of genistein on FAS was partially via the p38 pathway. On the other hand, genistein abolished the phosphorylation of janus-activated kinase 2 (JAK2) in response to MDI. AG490, a JAK2 inhibitor, suppressed the expression of CCAAT/enhancer binding protein alpha (C/EBPalpha), a marker of adipocyte differentiation. The findings suggest that genistein attenuates the differentiation of 3T3-L1 involving multiple signal pathways.