Effects of visual and aromatic stimulations on the perception of five fundamental tastes.

Taste perception is affected by various environmental factors. In the present study, we investigated the effects of visual and aromatic stimulations on stress responses and taste perception. Fourteen young healthy participants were assessed for stress levels and taste intensities under 5 different conditions: normal (no stimuli), watching an action scene, watching a forest scene, sniffing a rosemary aroma, and sniffing a lavender aroma. Compared to participants under the action scene condition, participants under the forest scene or under the rosemary aroma condition showed significantly lower stress levels. Furthermore, the forest scene condition significantly increased the saltiness intensity, whereas the rosemary aroma condition significantly increased the bitterness intensity. A positive or negative correlation was observed between the stress level and taste intensity of sourness and saltiness, respectively. These findings indicate that visual image and aroma have the potential to change taste perception as well as modulate stress conditions.

Genistein inhibits chondrogenic differentiation and mineralization of ATDC5 cells.

Isoflavones are phytoestrogens abundant in leguminous crops and are used to prevent a variety of hormonal disorders. In the present study, the effects of genistein and daidzein on the chondrogenic differentiation of ATDC5 cells were investigated. Genistein (10 µM) treatment markedly reduced production of sulfated proteoglycans and collagen fibers in the ATDC5 cells. Genistein suppressed the expression of genes involved in chondrocyte differentiation such as Sox9, Col2a1, Col10a1, Acan, and Tgfb1. Additionally, genistein significantly decreased calcium deposition in ATDC5 cells during chondrogenic differentiation; however, it increased calcification under non-chondrogenic mineralizing conditions. Daidzein exhibited a similar effect of suppressing chondrogenesis in ATDC5 cells, although its efficacy was 10-times lower than that of genistein. These findings suggest that a high concentration of genistein inhibits chondrogenesis and chondrogenic mineralization, whereas it enhances non-chondrogenic mineralization.

Menaquinone-4 Amplified Glucose-Stimulated Insulin Secretion in Isolated Mouse Pancreatic Islets and INS-1 Rat Insulinoma Cells.

Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, ß-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic ß-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects.

Efficacy of Platinum-Based Chemotherapy for Relapsed Small-Cell Lung Cancer after Amrubicin Monotherapy in Elderly Patients and Patients with Poor Performance Status.

BACKGROUND: Previous studies have shown amrubicin to be an effective first- or second-line treatment option for small-cell lung cancer (SCLC). However, there have been few studies reporting the efficacy of platinum-based chemotherapy after amrubicin therapy. We aimed to evaluate the efficacy of platinum-based chemotherapy as second-line treatment for elderly patients and those with SCLC with poor performance status (PS) previously treated with amrubicin monotherapy. METHODS: The records of SCLC patients who received platinum-based chemotherapy as a second-line chemotherapy after first-line treatment with amrubicin monotherapy were retrospectively reviewed and the treatment outcomes were evaluated. RESULTS: A total of 48 patients were enrolled in this study. Forty-one patients (85%) received carboplatin plus etoposide. The overall response rate was 39.6%. The median progression-free survival and overall survival were 3.7 and 7.6 months, respectively. The efficacy of the platinum-based regimen did not differ with the type of relapse after amrubicin monotherapy. The most common adverse events were hematological toxicities, including grade 3 or 4 neutropenia (38%), leukopenia (33%), and thrombocytopenia (10%). CONCLUSIONS: Platinum-based chemotherapy is potentially a valid treatment option for elderly patients or those with extensive-stage SCLC with poor PS as second-line chemotherapy, who progressed after first-line treatment with amrubicin monotherapy.

Biotin augments acetyl CoA carboxylase 2 gene expression in the hypothalamus, leading to the suppression of food intake in mice.

It is known that biotin prevents the development of diabetes by increasing the functions of pancreatic beta-cells and improving insulin sensitivity in the periphery. However, its anti-obesity effects such as anorectic effects remain to be clarified. Acetyl CoA carboxylase (ACC), a biotin-dependent enzyme, has two isoforms (ACC1 and ACC2) and serves to catalyze the reaction of acetyl CoA to malonyl CoA. In the hypothalamus, ACC2 increases the production of malonyl CoA, which acts as a satiety signal. In this study, we investigated whether biotin increases the gene expression of ACC2 in the hypothalamus and suppresses food intake in mice administered excessive biotin. Food intake was significantly decreased by biotin, but plasma regulators of appetite, including glucose, ghrelin, and leptin, were not affected. On the other hand, biotin notably accumulated in the hypothalamus and enhanced ACC2 gene expression there, but it did not change the gene expression of ACC1, malonyl CoA decarboxylase (a malonyl CoA-degrading enzyme), and AMP-activated protein kinase α-2 (an ACC-inhibitory enzyme). These findings strongly suggest that biotin potentiates the suppression of appetite by upregulating ACC2 gene expression in the hypothalamus. This effect of biotin may contribute to the prevention of diabetes by biotin treatment.

Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis.

Obesity rates continue to rise throughout the world. Recent evidence has suggested that environmental factors contribute to altered energy balance regulation. However, the role of epigenetic modifications to the central control of energy homeostasis remains unknown. To investigate the role of DNA methylation in the regulation of energy balance, we investigated the role of the de novo DNA methyltransferase, Dnmt3a, in Single-minded 1 (Sim1) cells, including neurons in the paraventricular nucleus of the hypothalamus (PVH). Dnmt3a expression levels were decreased in the PVH of high-fat-fed mice. Mice lacking Dnmt3a specifically in the Sim1 neurons, which are expressed in the forebrain, including PVH, became obese with increased amounts of abdominal and subcutaneous fat. The mice were also found to have hyperphagia, decreased energy expenditure, and glucose intolerance with increased serum insulin and leptin. Furthermore, these mice developed hyper-LDL cholesterolemia when fed a high-fat diet. Gene expression profiling and DNA methylation analysis revealed that the expression of tyrosine hydroxylase and galanin were highly upregulated in the PVH of Sim1-specific Dnmt3a deletion mice. DNA methylation levels of the tyrosine hydroxylase promoter were decreased in the PVH of the deletion mice. These results suggest that Dnmt3a in the PVH is necessary for the normal control of body weight and energy homeostasis and that tyrosine hydroxylase is a putative target of Dnmt3a in the PVH. These results provide evidence for a role for Dnmt3a in the PVH to link environmental conditions to altered energy homeostasis.

Cholesterol-Lowering and Antioxidant Effects of Pork-Liver Protein Hydrolysate in Otsuka Long-Evans Tokushima Fatty Rats.

In this study, we investigated the effects of a porcine liver protein hydrolysate (PLH) diet on lipid metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type II diabetes. OLETF rats (20-wk-old males) were pair-fed with either a PLH diet containing 20% PLH or a casein diet for 14 wk. Dietary PLH significantly lowered serum cholesterol and phospholipid concentrations, mainly by decreasing low-density lipoprotein and high-density lipoprotein fractions. Fecal cholesterol was significantly increased in the PLH diet group; however, the total bile acid concentration in the feces was not significantly different between the groups. In addition, the PLH diet significantly decreased serum thiobarbituric acid reactive substance concentrations. These results suggest that dietary PLH exerts hyperlipidemic and antioxidant effects, indicating that it is a novel functional food ingredient.

Effects of Pawpaw (Asimina triloba) Seed Extract on the Differentiation and Fat Accumulation of 3T3-L1 Cells under Different Glucose Conditions.

Asimina triloba (pawpaw) contains various bioactive alkaloids and acetogenins. In the present study, the effects of pawpaw seed extract (PSE) on adipocyte differentiation and fat accumulation were investigated in 3T3-L1 cells under different glucose conditions. Treatment of undifferentiated cells with 10 ng/mL PSE increased lactic acid production, suggesting enhanced anaerobic glycolysis. PSE treatment also suppressed cell proliferation and decreased the nicotinamide adenine dinucleotide (NAD)+/NADH ratio in low-glucose medium; however, this effect was not observed in high-glucose medium. Additionally, PSE treatment under low-glucose conditions resulted in reduced accumulation of triglycerides and decreased expression of peroxisome proliferator-activated receptor (PPAR)-γ, CAAT/enhancer-binding protein (C/EBP)-α, and sterol regulatory element binding protein (SREBP)-1c in adipocyte-differentiated cells. PSE exerted greater effects on adipocyte differentiation and triglyceride content in 3T3-L1 cells under low-glucose conditions than under high-glucose conditions. These findings indicate that PSE enhances anaerobic glycolysis and inhibits adipocyte differentiation and fat accumulation in 3T3-L1 cells under glucose-restricted conditions.

Effects of Collagen Peptide Administration on Visceral Fat Content in High-Fat Diet-Induced Obese Mice.

Collagen peptides (CPs) are bioactive molecules that have beneficial effects on bone metabolism and against joint disorders. In the present study, we investigated the effect of CP supplementation on visceral fat mass and plasma lipid concentrations in high-fat diet (HFD)-induced obese mice. Male ddY mice were fed a normal diet or HFD for 3 wk, and assigned to N or NCP groups and to F or FCP groups, respectively. The NCP and FCP group mice were administered experimental diets containing 25 mg/g CPs for 3 wk further. During the experimental period, CP supplementation affected neither the food consumption nor the body weight of the mice. No significant differences in the plasma triglyceride, non-esterified fatty acid, and cholesterol concentrations were observed among all the groups. In contrast, the weight of testicular fat mass was significantly decreased in the FCP group as compared with that in the F group. The expression levels of leptin and tumor necrosis factor (TNF)-α genes in the adipose tissue correlated with the visceral fat mass, although these differences were not significant. These findings indicate that CPs may have a reducing effect on visceral fat content but are less effective in reducing body weight.

Effects of administration of glucosamine and chicken cartilage hydrolysate on rheumatoid arthritis in SKG mice.

Supplementation with cartilage constituents, such as glucosamine, chondroitin sulfate and collagen peptide, are believed to reduce pain associated with joint disorders, such as rheumatoid arthritis (RA). Here, we administered daily, 10 mg glucosamine or 100 mg chicken cartilage hydrolysate (CH) to SKG/Jcl mice, a model for spontaneous RA, for 5 weeks and evaluated their effects on RA development. In SKG mice, the administration of glucosamine had no reducing effect on RA score but suppressed the expression of Mmp13 and Col3a1 genes in articular cartilage. In contrast, administration of CH suppressed the RA score and levels of plasma interleukin-6 and interleukin-17 to half, although the differences were not significant. Mice administered with glucosamine also showed decreased bone strength of femur and these adverse effects could be eliminated when glucosamine was used in conjunction with CH. These results suggest that CH and glucosamine exert effects on different aspects in SKG mice.

Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons.

Ghrelin, an orexigenic hormone, directly activates neuropeptide (NPY) neurons in the hypothalamic arcuate nucleus (ARC), and thereby stimulates food intake. The hypothalamic level of AMP-activated protein kinase (AMPK), an intracellular energy sensor, is activated by peripheral and central administration of ghrelin. We examined whether ghrelin regulates AMPK activity in NPY neurons of the ARC. Single neurons were isolated from the ARC and cytosolic Ca(2+) concentration ([Ca(2+)](i)) was measured by fura-2 microfluorometry, followed by immunocytochemical identification of NPY, phospho-AMPK, and phospho-acetyl-CoA carboxylase (ACC). Ghrelin and AICAR, an AMPK activator, increased [Ca(2+)](i) in neurons isolated from the ARC. The ghrelin-responsive neurons highly overlapped with AICAR-responsive neurons. The neurons that responded to both ghrelin and AICAR were primarily NPY-immunoreactive neurons. Treatment with ghrelin increased phosphorylation of AMPK and ACC. An AMPK inhibitor, compound C, suppressed ghrelin-induced [Ca(2+)](i) increases. These results demonstrate that ghrelin increases [Ca(2+)](i) via AMPK-mediated signaling in the ARC NPY neurons.

Liver injury due to 3-amino-1-methyl-5h-pyrido [4,3-b] indole (Trp-P-2) and its prevention by miso.

Trp-P-2(3-amino-1-methyl-5H-pyrido [4,3-b] indole) ingestion for 42 d by C3H/HeJJcl mice caused elevation of serum alanine transaminase (ALT) activity and several signs of liver injury. These alterations were not observed in mice fed the diet supplemented with 10% miso. This suggests a preventive effect of miso as to Trp-P-2 induced liver injury.

Amrubicin monotherapy for elderly patients with relapsed extensive-disease small-cell lung cancer: A retrospective study.

BACKGROUND: Previous studies have shown amrubicin (AMR) to be an effective second-line treatment option for small-cell lung cancer (SCLC). However, the efficacy of AMR in elderly patients with relapsed SCLC has not been sufficiently evaluated. METHODS: The medical records of elderly patients with relapsed SCLC who received AMR as second-line chemotherapy were retrospectively reviewed, and their treatment outcomes were evaluated. RESULTS: Thirty-one patients with a median age of 72 years (22 patients with sensitive relapse and 9 with refractory relapse) were analyzed. The median number of treatment cycles was four (range: 1-10), and the response rate was 29%. The median progression-free survival (PFS) and overall survival (OS) were 5.4 and 11.6 months, respectively. The OS of 22 patients who received third-line chemotherapy was 15.5 months. The PFS (6.2 vs. 3.2 months; P = 0.002) and OS (14.8 vs. 5.7 months; P = 0.004) were significantly longer in patients with sensitive relapse than those with refractory relapse. The frequency of grade 3 or higher neutropenia was high (n = 18, 58%), while febrile neutropenia was only observed in five patients (16%). Non-hematological toxic effects were relatively mild, and pneumonitis and treatment-related deaths were not observed. CONCLUSION: AMR may be a feasible and effective regimen for elderly patients with relapsed SCLC.

Comparison of carboplatin plus etoposide with amrubicin monotherapy for extensive-disease small cell lung cancer in the elderly and patients with poor performance status.

BACKGROUND: Carboplatin plus etoposide (CE) is a standard treatment for elderly patients with extensive-disease small cell lung cancer (ED-SCLC). However, amrubicin monotherapy (AMR) may be a feasible alternative. We compared the efficacies and safety profiles of CE and AMR for ED-SCLC in elderly patients and chemotherapy-naive patients with poor performance status (PS). METHODS: The records of SCLC patients who received CE or AMR as first-line chemotherapy were retrospectively reviewed and their treatment outcomes evaluated. RESULTS: Eighty-four patients (median age 72 years; 42 each received CR and AMR) were analyzed; 34 patients had a PS score of 2. There were no significant differences in patient characteristics between the treatment groups. The median progression-free survival rates of patients in the CE and AMR groups were 5.8 and 4.8 months, respectively (P = 0.04); overall survival was 14.0 and 8.5 months, respectively (P = 0.089). Twenty-three CE group patients received AMR as second-line chemotherapy; their median overall survival from first-line chemotherapy was 18.5 months. Grade 3 or higher neutropenia occurred more frequently in patients treated with AMR (64% vs. 40%; P = 0.02), as did febrile neutropenia (14% vs. 7%). CONCLUSIONS: CE remains a suitable first-line treatment for ED-SCLC in elderly patients or those with poor PS in comparison with AMR.

Real-world evaluation of carboplatin plus a weekly dose of nab-paclitaxel for patients with advanced non-small-cell lung cancer with interstitial lung disease.

BACKGROUND: The optimal chemotherapy regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remains unknown. Therefore, in this study, we investigated the real-world efficacy and safety of carboplatin (CBDCA) plus nab-paclitaxel (nab-PTX) as a first-line regimen for NSCLC patients with ILD. PATIENTS AND METHODS: We retrospectively reviewed advanced NSCLC patients with ILD who had received CBDCA plus nab-PTX as a first-line chemotherapy regimen between April 2013 and March 2018. Patients were diagnosed with ILD based on the findings of a pretreatment high-resolution computed tomography of the chest. RESULTS: The 34 patients enrolled in this study were included in the efficacy and safety analysis. Collagen vascular disease or a history of exposure to dust or asbestos was not reported for any patients. The median age of patients was 71 years (range, 59-83 years), and 32 patients had a performance status of 0 or 1. The overall response rate was 38.2%. The median progression-free survival and overall survival were 5.8 months and 12.7 months, respectively. Chemotherapy-related acute exacerbation of ILD was observed in two patients (5.7%). Other toxicities were feasible, and no treatment-related deaths occurred. CONCLUSION: CBDCA plus nab-PTX, as a first-line chemotherapy regimen for NSCLC, showed favorable efficacy and safety in patients with preexisting ILD.

Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance.

The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered. Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet-induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes.

The Effects of Light and Temperature on Biotin Synthesis in Pea Sprouts.

Biotin is an essential micronutrient, and is a cofactor for several carboxylases that are involved in the metabolism of glucose, fatty acids, and amino acids. Because plant cells can synthesize their own biotin, a wide variety of plant-based foods contains significant amounts of biotin; however, the influence of environmental conditions on the biotin content in plants remains largely unclear. In the present study, we investigated the effects of different cultivation conditions on the biotin content and biotin synthesis in pea sprouts (Pisum sativum). In the experiment, the pea sprouts were removed from their cotyledons and cultivated by hydroponics under five different lighting and temperature conditions (control [25ºC, 12-h light/12-h dark cycle], low light [25ºC, 4-h light/20-h dark cycle], dark [25ºC, 24 h dark], low temperature [12ºC, 12-h light/12-h dark cycle], and cold [6ºC, 12-h light/12-h dark cycle]) for 10 d. Compared to the biotin content of pea sprouts under the control conditions, the biotin contents of pea sprouts under the low-light, dark, and cold conditions had significantly decreased. The dark group showed the lowest biotin content among the groups. Expression of the biotin synthase gene (bio2) was also significantly decreased under the dark and cold conditions compared to the control condition, in a manner similar to that observed for the biotin content. No significant differences in the adenosine triphosphate content were observed among the groups. These results indicate that environmental conditions such as light and temperature modulate the biotin content of pea plant tissues by regulating the expression of biotin synthase.

Polymorphism, heteroplasmy, mitochondrial fusion and diabetes.

Mitochondrial DNA (mtDNA) is highly susceptible to mutations that result in polymorphisms and diseases including diabetes. We analyzed heteroplasmy, polymorphisms related to diabetes, and complementation by fusogenic proteins. Cytoplast fusion and microinjection allow, defects in mutated mtDNA inside a heteroplasmic cell to be complemented by fusing two mitochondria via human fusogenic proteins. We characterized three hfzos as well as two OPAls that prevent apoptosis. Two coiled coil domains and GTPase domains in these fusogenic proteins regulate membrane fusion. The hfzo genes were expressed mainly in the brain and in muscle that are postmitotic, but not in the pancreas. Under the influence of polymorphisms of mtDNA and nDNA, the vicious circle of reactive oxygen species and mutations in cell can be alleviated by mitochondrial fusion.

Exogenous and endogenous ghrelin counteracts GLP-1 action to stimulate cAMP signaling and insulin secretion in islet ß-cells.

We studied interactive effects of insulinotropic GLP-1 and insulinostatic ghrelin on rat pancreatic islets. GLP-1 potentiated glucose-induced insulin release and cAMP production in isolated islets and [Ca(2+)](i) increases in single ß-cells, and these potentiations were attenuated by ghrelin. Ghrelin suppressed [Ca(2+)](i) responses to an adenylate cyclase activator forskolin. Moreover, GLP-1-induced insulin release and cAMP production were markedly enhanced by [D-lys(3)]-GHRP-6, a ghrelin receptor antagonist, in isolated islets. These results indicate that both exogenous and endogenous islet-derived ghrelin counteracts glucose-dependent GLP-1 action to increase cAMP production, [Ca(2+)](i) and insulin release in islet ß-cells, positioning ghrelin as a modulator of insulinotropic GLP-1.