Sesame lignans increase sympathetic nerve activity and blood flow in rat skeletal muscles.

Beneficial effects of sesame lignans, especially antioxidative effects, have been widely reported; however, its potential effects on autonomic nerves have not yet been investigated. Therefore, the current study aimed to investigate the effect of sesame lignans on the autonomic nervous system. The sympathetic nerve activity in rat skeletal muscle was measured using electrophysiological approaches, with blood flow determined using the laser Doppler method. Sesame lignans were administered intragastrically at 2 and 20 mg/kg, and after 60 min, the sympathetic nerve activity was observed to increase by 45.2% and 66.1%, respectively. A significant increase in blood flow (39.6%) was also observed for the 20-mg/kg dose when measured at 55 min after administration. These sympathomimetic effects were completely prevented by subdiaphragmatic vagotomy, and the increase in blood flow was eliminated in the presence of the beta2-adrenergic receptor inhibitor butoxamine. Thus, it is proposed that sesame lignans can increase the blood flow of skeletal muscle, possibly by exciting sympathetic nerve activity through the afferent vagal nerve.

Intake of 25-Hydroxyvitamin D3 Reduces Duration and Severity of Upper Respiratory Tract Infection: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Comparison Study.

OBJECTIVES: This study aimed to assess the effect of 25-hydroxyvitamin D3 (25OHD) which is a hydroxide of vitamin D3 ingestion on upper respiratory tract infection (URTI). DESIGN AND SETTING: A prospective, randomized, double-blind, placebo-controlled study was performed from December 2015 to September 2016 in the Nihonbashi Egawa Clinic, Kei Medical Office TOC Building Medical Clinic, and Medical Corporation Kaiseikai Kita-Shinyokohama Medical Clinic, in Japan. PARTICIPANTS: Four hundred twenty eight participants aged 45-74 years were screened by their serum 25-hydoroxyvitamin D concentration. INTERVENTION: The participants were randomized to either 25OHD (10 µg/day) or placebo capsule, daily, for 16 consecutive weeks. MEASUREMENTS: The primary outcome measure was the incidence proportion of URTI, and the secondary outcome measures were the physical severity score, the quality-of-life (QOL) score, the duration of URTI, and the incidence proportion of new URTI events every four weeks. Data were collected using cold diary Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) during the intervention. RESULTS: Of 428 participants screened, 252 with serum 25-hydroxyvitamn D levels were deficient or insufficient (75 nmol/L or less) were enrolled in this study. Of these, 105 placebo and 110 25OHD group subjects completed the study. For the incidence proportion of URTI, no effect of 25OHD intake was observed. On the other hand, the duration of URTI was shorter in the 25OHD (P = 0.061) compared to placebo. For the incidence proportion of URTI every four weeks, the incidence of new URTI was decreased in both groups over the time of intake. However, when the 25OHD and the placebo were compared, a decrease in the incidence proportion of URTI was seen earlier in the 25OHD. When the total physical severity score and the total QOL score during the study were assessed, they both were significantly improved in the 25OHD compared to placebo. CONCLUSIONS: The intake of 25OHD may reduce the duration of URTI, the physical severity, and the QOL when suffering from URTI.

Response to comments on "Local impermeant anions establish the neuronal chloride concentration".

We appreciate the interest in our paper and the opportunity to clarify theoretical and technical aspects describing the influence of Donnan equilibria on neuronal chloride ion (Cl(-)) distributions.

Local impermeant anions establish the neuronal chloride concentration.

Neuronal intracellular chloride concentration [Cl(-)](i) is an important determinant of γ-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl(-) across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl(-)](i). Measurement of [Cl(-)](i) in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A](i)) and polyanionic extracellular matrix glycoproteins ([A](o)) constrain the local [Cl(-)]. CCC inhibition had modest effects on [Cl(-)](i) and neuronal volume, but substantial changes were produced by alterations of the balance between [A](i) and [A](o). Therefore, CCCs are important elements of Cl(-) homeostasis, but local impermeant anions determine the homeostatic set point for [Cl(-)], and hence, neuronal volume and the polarity of local GABA(A)R signaling.

Adiponectin gene single-nucleotide polymorphisms and treatment response to obesity.

BACKGROUND: In the adiponectin gene polymorphisms, single-nucleotide polymorphism (SNP)-45 and SNP276 have reportedly been associated with obesity, Type 2 diabetes, and other features of metabolic syndrome. AIM: Whether these adiponectin SNP affect obesity-related parameters during caloric restriction in obese subjects. SUBJECTS AND METHODS: Thirty- two obese Japanese women were treated by meal replacement with a low calorie diet for 8 weeks and asked to maintain their habitual lifestyle. Obesity-related parameters were measured before and after the treatment period. We determined four SNP (T45G, I164T, G276T, and C-11377G) using a fluorescent allele-specific DNA primer assay systemand FRET probe assay system. RESULTS: After the treatment, the extent of decrease in waist circumference was greater in the subjects with the G/G or G/T genotype of SNP276 than in those with the T/T genotype (p=0.026). As for SNP45, the extent of decrease in triglyceride levels was greater in the subjects with the T/T genotype than in those with the T/G genotype (p=0.003). For SNP-11377, the extent of decrease in systolic blood pressure and fasting plasma glucose was greater in the subjects with the C/G or G/G genotype than in those with the C/C genotype (p=0.044). CONCLUSION: Our findings indicate that each SNP in the adiponectin gene might modify the change in obesity-related parameters during meal replacement with a low calorie diet.

Membrane localization of protein-tyrosine phosphatase 1B is essential for its activation of sterol regulatory element-binding protein-1 gene expression.

Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor in stimulating lipogenesis in the liver. Protein-tyrosine phosphatase 1B (PTP1B) induces SREBP-1 gene expression via protein phosphatase 2A (PP2A) activation. PTP1B is reported to be anchored on the endoplasmic reticulum (ER) via its C-terminal tail, and change in intracellular localization of PTP1B by C-terminal-truncation did not alter its inhibitory effects on insulin signaling. In this study, we investigated whether the change in intracellular localization of PTP1B could influence SREBP-1 gene expression. Overexpression of C-terminal truncated PTP1B (PTP1BdeltaCT) in rat Fao cells did not induce SREBP-1 gene expression. Furthermore, PTP1BdeltaCT failed to bind PP2A, resulting in impaired PP2A activation, whereas overexpression of wild-type PTP1B (PTP1BWT) associated with PP2A. Moreover, a membrane-targeted PTP1BDeltaCT activated PP2A with restored PP2A binding, despite the absence of its C-terminal region. Finally, overexpression of PTP1BdeltaCT into mouse primary cultured hepatocytes failed to enhance SREBP-1c mRNA, whereas membrane-targeted PTP1BdeltaCT led to enhanced SREBP-1c mRNA in hepatocytes as well as PTP1BWT. In conclusion, membrane localization of PTP1B is essential for PP2A activation, which is crucial for its enhancement of SREBP-1 gene expression.

Effect of corosolic acid on postchallenge plasma glucose levels.

Corosolic acid (CRA) is a substance extracted from Lagerstroemia speciosa L. and has been reported to have biological activities in in vitro and experimental animal studies. In this study, 31 subjects were orally administered 10mg CRA or a placebo, on different occasions, in a capsule 5min before the 75-g oral glucose tolerance test (OGTT) in a double-blind and cross-over design. Nineteen subjects had diabetes, seven had impaired glucose tolerance, one had impaired fasting glucose, and four had normal glucose tolerance according to the 1998 WHO criteria. There were no significant differences in plasma glucose levels before and 30min after the administration. CRA treatment subjects showed lower glucose levels from 60min until 120min and reached statistical significance at 90min. In this study, we have shown for the first time that CRA has a lowering effect on postchallenge plasma glucose levels in vivo in humans.

The effect of adding calcium lactate to xylitol chewing gum on remineralization of enamel lesions.

The purpose of the study was to determine whether adding calcium lactate to chewing gum containing xylitol enhances remineralization of enamel surfaces using an early caries lesion model. Enamel slabs were cut from human extracted sound teeth and artificial subsurface lesions created within each. Half the enamel slabs were used as controls and stored in a humidifier while half were mounted into oral appliances worn by 10 volunteers (22-27 years old, 2 males and 8 females) in a three-leg trial, during which they wore the appliance without chewing gum, chewed gum containing xylitol + calcium lactate or chewed gum containing only xylitol 4 times a day for 2 weeks. Calcium concentrations in the enamel surfaces of control and test slabs were measured by X-ray spectrometry and degrees of remineralization were calculated. The mean degree of remineralization was greater after chewing xylitol-Ca gum (0.46 +/- 0.10) than after no gum (0.16 +/- 0.14) or after chewing xylitol gum (0.33 +/- 0.10) (p < 0.01). In conclusion, chewing gum containing xylitol + calcium lactate could enhance remineralization of enamel surface compared to chewing gum containing only xylitol or no gum chewing.

Human papillomavirus-associated plantar epidermoid cyst related to epidermoid metaplasia of the eccrine duct epithelium: a combined histological, immunohistochemical, DNA-DNA in situ hybridization and three-dimensional reconstruction analysis.

BACKGROUND: We recently proposed that certain palmoplantar epidermoid cysts may be related to eccrine ducts and that human papillomavirus (HPV) 60 may play a role in their pathomechanism. However, the origin of palmoplantar epidermoid cysts is still controversial. OBJECTIVES: To examine the contribution of eccrine ducts and HPV 60 in the development of epidermoid cysts. METHODS: Five epidermoid cysts and four ridged warts that had developed on the soles of a patient were studied histologically, immunohistochemically and by DNA-DNA in situ hybridization. Using serial sections obtained from its entire body, a three-dimensional reconstruction (3DR) analysis was performed on the smallest cyst to analyse the relationship between the epidermoid cyst, eccrine duct and the overlying epidermis. RESULTS: Histological and DNA-DNA in situ hybridization analyses demonstrated both homogeneous intracytoplasmic inclusion bodies pathognomonic for HPV 60 infection and HPV 60 DNA sequences not only in all of the epidermoid cysts and ridged warts but also in the acrosyringeal portion of an eccrine duct, with the dermal portion of which the smallest cyst had been revealed to connect by 3DR analysis. However, immunohistochemical analyses using antibodies against human carcinoembryonic antigen (CEA), involucrin and several cytokeratins (CKs) revealed that the immunoreactivity of the cyst was not identical to that of the eccrine dermal duct but was identical to that of suprabasal layers of the epidermis. CONCLUSIONS: It was clearly demonstrated that an HPV 60-associated epidermoid cyst with immunoreactivities for CEA, involucrin and CKs which were identical to those of the epidermis connected with the eccrine dermal duct, supporting the idea that certain palmoplantar epidermoid cysts may develop following the epidermoid metaplasia of eccrine ducts with HPV 60 infection.

Eccrine-centred distribution of human papillomavirus 63 infection in the epidermis of the plantar skin.

BACKGROUND: The primary target cell of human papillomaviruses (HPVs) is an unsettled issue. Recent studies have suggested that the hair follicle is an important candidate as the reservoir of certain HPV types. However, little is known about the cells which serve as the target or the reservoir of HPVs in nonhairy palmoplantar skin. OBJECTIVES: To investigate whether the eccrine sweat gland, the only skin appendage in nonhairy palmoplantar skin, also serves as the target or the reservoir of HPVs. METHODS: HPV 63-induced warts were employed in this study, because the virus induces tiny warty lesions of a punctuate appearance in the plantar skin and shows peculiar intracytoplasmic inclusion bodies as a diagnostic histopathological marker of infection: this seemed to provide a useful model for the present study. Serial sections were obtained from the entire body of each biopsy specimen and were investigated histologically, immunohistochemically and using DNA-DNA in situ hybridization (ISH) for the histological localization of HPV 63 infection. RESULTS: On microscopy, HPV 63 histopathological changes were seen closely associated with eccrine ducts. Using ISH, HPV 63 DNA was detected not only in keratinocytes resident around acrosyringia but also in the uppermost portion of the eccrine dermal duct. A few keratinocytes harbouring HPV 63 DNA were also identified in acrosyringeal areas in the normal plantar skin adjacent to the wart lesions. CONCLUSIONS: On the basis of our results, it seems likely that HPV 63 targets keratinocytes resident in or around the eccrine ducts in the plantar skin. The results may also suggest that not only hair follicles but also eccrine ducts serve as reservoirs for certain HPV types, including HPV 63, especially in the nonhairy plantar skin.

Three dimensional ultrastructure of transverse (Harris) lines in the long bone.

To investigate the occurrence of transverse lines in long bones of adults, we studied 27 cadavers (14 males and 13 females). After confirming the presence of a transverse line, a cross-sectional sample was examined macroscopically, and by soft X-ray and scanning electron microscopy. The following results were obtained: 1. According to roentgenograms, transverse (Harris') lines were observed in 40.7% of the distal half of the femur and in 29.6% of the proximal half of the tibia. 2. Macroscopic examination of the bone cross-sections at the level of the transverse line showed various membranous structures. 3. In scanning electron micrographs, no marked difference in structure was observed between the transverse line trabeculae and the compact bone.

Gene expression analysis in human monocytes, monocyte-derived dendritic cells, and alpha-galactosylceramide-pulsed monocyte-derived dendritic cells.

In vitro proliferation and functional activation of V alpha 24NKT cells following stimulation with alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells (DCs) have been observed. Because little is known about the molecular events on DCs following interaction with alpha-GalCer, we performed gene expression profiling of 2400 genes in monocytes and monocyte-derived immature DCs pulsed with alpha-GalCer (alpha-GalCer-imDCs). Overall, the expression levels of 48 genes were up-regulated and 28 were down-regulated in alpha-GalCer-imDCs. Semiquantitative RT-PCR analysis on monocytes, imDCs, alpha-GalCer-imDCs, and mature DCs confirmed the up- and down-regulation of the mRNA expression levels of 28 selected genes. Notably, we identified the specific up-regulation of mRNA expression levels of ribonuclease A and collapsin response mediator protein upon the stimulation of imDC with alpha-GalCer, suggesting a novel immunomodulating effect of alpha-GalCer on imDCs. In this study, we used imDCs prepared by culturing of monocytes with GM-CSF and IL-4 for 5 days and mDCs prepared by further culturing of imDCs with TNF alpha for two extra days.

Increased arterial wall stiffness limits flow volume in the lower extremities in type 2 diabetic patients.

OBJECTIVE: To document an association between arterial wall stiffness and reduced flow volume in the lower-extremity arteries of diabetic patients. RESEARCH DESIGN AND METHODS: We recruited 60 consecutive type 2 diabetic patients who had no history or symptoms of peripheral arterial disease (PAD) in the lower extremities and normal ankle/brachial systolic blood pressure index at the time of the study (non-PAD group) and 20 age-matched nondiabetic subjects (control group). We used an automatic device to measure pulse wave velocity (PWV) in the lower extremities as an index of arterial wall stiffness. At the popliteal artery, we evaluated flow volume and the resistive index as an index of arterial resistance to blood flow using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. RESULTS: Consistent with previous reports, we confirmed that the non-PAD group had an abnormally higher PWV compared with that of the control group (P < 0.001). To further demonstrate decreased flow volume and abnormal flow pattern at the popliteal artery in patients with a higher degree of arterial wall stiffness, we assigned the 60 non-PAD patients to tertiles based on their levels of PWV. In the highest group, magnetic resonance angiograms of the calf and foot arteries showed decreased intravascular signal intensity, indicating the decreased arterial inflow in those arteries. The highest group was also characterized by the lowest late diastolic and total flow volumes as well as the highest resistive index among the groups. From stepwise multiple regression analysis, PWV and autonomic function were identified as independent determinants for late diastolic flow volume (r(2) = 0.300; P < 0.001). CONCLUSIONS: Arterial wall stiffness was associated with reduced arterial flow volume in the lower extremities of diabetic patients.

Insulin-induced c-Jun N-terminal kinase activation is negatively regulated by protein kinase C delta.

We investigated the role of protein kinase C (PKC) in insulin-induced c-Jun N-terminal kinase (JNK) activation in rat 1 fibroblasts expressing human insulin receptors. Insulin treatment led to increased SAPK/ERK kinase 1 (SEK1) phosphorylation, and then stimulated JNK activity in a dose- and time-dependent manner, as measured either by a solid-phase kinase assay using glutathione S-transferase (GST)-c-Jun fusion protein as a substrate, or by quantitation of the levels of phosphorylated JNK by Western blotting using anti-phospho-JNK antibody. Insulin-induced JNK activation was potentiated by either preincubating cells with 2 nM GF109203X (PKC inhibitor) or down-regulation of PKC by overnight treatment with 100 nM tetradecanoyl phorbol acetate. In contrast, brief preincubation with 100 nM tetradecanoyl phorbol acetate inhibited the insulin- induced JNK activation. Furthermore, we found that 5 microM rottlerin, a PKCdelta inhibitor, enhanced insulin-induced JNK activation, but a PKCbeta inhibitor, LY333531, had no effect. Consistent with these findings, overexpression of PKCdelta led to decreased insulin-induced JNK activation, whereas overexpression of PKCbeta had no effect. Although overexpression of wild-type PKCdelta attenuated insulin-induced JNK activation, a kinase-dead PKCdelta mutant did not cause such attenuation. Finally, we found that the magnitude of insulin-induced JNK activation was inversely correlated with the expression level of PKCdelta among different cell lines. In conclusion, the expression of PKCdelta may negatively regulate insulin-induced JNK activation.

Insulin production in a neuroectodermal tumor that expresses islet factor-1, but not pancreatic-duodenal homeobox 1.

We studied a 60-yr-old female with a brain tumor who showed severe symptoms of hypoglycemia (plasma glucose, 2.2 mmol/L) and hyperinsulinemia (1.28 nmol/L) after radiotherapy. The cystic brain tumor contained proinsulin and insulin at concentrations of 13.6 and 1.22 nmol/L, respectively. Immunohistochemical studies showed the tumor cells were ectodermal in origin but not endodermal, based on three diagnostic features of neuroectodermal tumors 1) pseudorosette formation noted under light microscopy, 2) finding of a small number of dense core neurosecretory granules on electron microscopy, and 3) positive immunostaining for both neuronal specific enolase and protein gene product 9.5. These cells also expressed the transcription factor, neurogenin-3, NeuroD/beta 2, and islet factor I, which are believed to be transcription factors in neuroectoderm as well as in pancreatic islet cells, but not pancreatic-duodenal homeobox 1, Pax4, or Nkx2.2. In addition, they did not express glucagon, somatostatin, or glucagon-like peptide-1. Our results show the presence of proinsulin in an ectoderm cell brain tumor that does not express the homeobox gene, pancreatic-duodenal homeobox 1, but expresses other transcription factors, i.e. neurogenin3, NeuroD/beta 2, and islet factor-1, which are related to insulin gene expression in the brain tumor.

Protein-tyrosine phosphatase-1B negatively regulates insulin signaling in l6 myocytes and Fao hepatoma cells.

Insulin signaling is regulated by tyrosine phosphorylation of the signaling molecules, such as the insulin receptor and insulin receptor substrates (IRSs). Therefore, the balance between protein-tyrosine kinases and protein-tyrosine phosphatase activities is thought to be important in the modulation of insulin signaling in insulin-resistant states. We thus employed the adenovirus-mediated gene transfer technique, and we analyzed the effect of overexpression of a wild-type protein-tyrosine phosphatase-1B (PTP1B) on insulin signaling in both L6 myocytes and Fao cells. In both cells, PTP1B overexpression blocked insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 by more than 70% and resulted in a significant inhibition of the association between IRS-1 and the p85 subunit of phosphatidylinositol 3-kinase and Akt phosphorylation as well as mitogen-activated protein kinase phosphorylation. Moreover, insulin-stimulated glycogen synthesis was also inhibited by PTP1B overexpression in both cells. These effects were specific for insulin signaling, because platelet-derived growth factor (PDGF)-stimulated PDGF receptor tyrosine phosphorylation and Akt phosphorylation were not inhibited by PTP1B overexpression. The present findings demonstrate that PTP1B negatively regulates insulin signaling in L6 and Fao cells, suggesting that PTP1B plays an important role in insulin resistance in muscle and liver.