Coffee and metabolic phenotypes: A cross-sectional analysis of the Japan multi-institutional collaborative cohort (J-MICC) study.

BACKGROUND AND AIMS: To date, the relationship between coffee consumption and metabolic phenotypes has hardly been investigated and remains controversial. Therefore, the aim of this cross-sectional study is to examine the associations between coffee consumption and metabolic phenotypes in a Japanese population. METHODS AND RESULTS: We analyzed the data of 26,363 subjects (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Coffee consumption was assessed using a questionnaire. Metabolic Syndrome (MetS) was defined according to the Joint Interim Statement Criteria of 2009, using body mass index (BMI) instead of waist circumference. Subjects stratified by the presence or absence of obesity (normal weight: BMI <25 kg/m2; obesity: BMI ≥25 kg/m2) were classified by the number of MetS components (metabolically healthy: no components; metabolically unhealthy: one or more components) other than BMI. In multiple logistic regression analyses adjusted for sex, age, and other potential confounders, high coffee consumption (≥3 cups/day) was associated with a lower prevalence of MetS and metabolically unhealthy phenotypes both in normal weight (OR 0.83, 95% CI 0.76-0.90) and obese subjects (OR 0.83, 95% CI 0.69-0.99). Filtered/instant coffee consumption was inversely associated with the prevalence of MetS and metabolically unhealthy phenotypes, whereas canned/bottled/packed coffee consumption was not. CONCLUSION: The present results suggest that high coffee consumption, particularly filtered/instant coffee, is inversely associated with the prevalence of metabolically unhealthy phenotypes in both normal weight and obese Japanese adults.

Effect of herbal medicine daikenchuto on gastrointestinal symptoms following laparoscopic colectomy in patients with colon cancer: A prospective randomized study.

We conducted a prospective randomized study to investigate the effect of daikenchuto (DKT) on abdominal symptoms following laparoscopic colectomy in patients with left-sided colon cancer. Patients who suffered from abdominal pain or distention on postoperative day 1 were randomized to either the DKT group or non-DKT group. The primary endpoints were the evaluation of abdominal pain, abdominal distention, and quality of life. The metabolome and gut microbiome analyses were conducted as secondary endpoints. A total of 17 patients were enrolled: 8 patients in the DKT group and 9 patients in the non-DKT group. There were no significant differences in the primary endpoints and postoperative adverse events between the two groups. The metabolome and gut microbiome analyses showed that the levels of plasma lipid mediators associated with the arachidonic acid cascade were lower in the DKT group than in the non-DKT group, and that the relative abundance of genera Serratia and Bilophila were lower in the DKT group than in the non-DKT group. DKT administration did not improve the abdominal symptoms following laparoscopic colectomy. The effects of DKT on metabolites and gut microbiome have to be further investigated.

Preventive Effect of Antioxidative Nutrient-Rich Enteral Diet Against Liver Ischemia and Reperfusion Injury.

BACKGROUND: Liver ischemia and reperfusion injury (IRI) is a major problem associated with liver surgery. This study is aimed to compare the preventive effect of an antioxidative nutrient-rich enteral diet (Ao diet) with an ordinal enteral diet (control diet) against liver IRI. METHODS: The Ao diet was an ordinary diet comprising polyphenols (catechin and proanthocyanidin) and enhanced levels of vitamins C and E. Male C57BL/6 mice were fed the Ao or control diet for 7 days before ischemic insult for 60 minutes, followed by reperfusion for 6 hours. The levels of inflammatory cytokines, chemokines, and antioxidant enzymes and oxidative stress were evaluated. RESULTS: After 7 days of pretreatment with the Ao diet, the serum levels of vitamins C and E in mice were markedly elevated. The levels of serum aspartate aminotransferase and alanine aminotransferase, as well as the scores of liver necrosis caused by ischemia and reperfusion, were significantly lower in the Ao diet group than in the control diet group. The gene expression levels of inflammatory cytokines and chemokines, such as interleukin-6 and CXCL1, were significantly lower in the Ao diet group. In the liver, the levels of antioxidant enzymes superoxide dismutase 1 (SOD1) and SOD2 were significantly higher and the malondialdehyde levels were significantly lower in the Ao diet group. Cell adhesion molecule expression was significantly lower, and neutrophil and macrophage infiltration was less in the Ao diet group. CONCLUSIONS: Antioxidative nutrient supplementation to an ordinary enteral diet may mitigate liver IRI by causing an antioxidant effect and suppressing inflammation.

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry.

In situ click chemistry is a target-guided synthesis technique for discovering potent protein ligands by assembling azides and alkynes into triazoles inside the affinity site of a target protein. We report the rapid discovery of a new and potent inhibitor of bacterial chitinases by the use of in situ click chemistry. We observed a target-templated formation of a potent triazole inhibitor of the chitinase-catalyzed chitin hydrolysis, through in situ click chemistry between a biologically active azide-containing scaffold and structurally unrelated alkyne fragments. Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides and antiasthmatics. Argifin, which has been isolated and characterized as a cyclopentapeptide natural product by our research group, shows strong inhibitory activity against chitinases. As a result of our efforts at developing a chitinase inhibitor from an azide-bearing argifin fragment and the application of the chitinase template and a library of alkynes, we rapidly obtained a very potent and new 1,5-disubstituted triazole inhibitor against Serratia marcescens chitinase (SmChi) B. The new inhibitor expressed 300-fold increase in the inhibitory activity against SmChiB compared with that of argifin. To the best of our knowledge, our finding of an enzyme-made 1,5-disubstituted triazole, using in situ click chemistry is the second example reported in the literature.

Increased susceptibility to diet-induced obesity in histamine-deficient mice.

BACKGROUND AND AIM: The neurotransmitter histamine is involved in the regulation of appetite and in the development of age-related obesity in mice. Furthermore, histamine is a mediator of the anorexigenic action of leptin. The aim of the present study was to investigate a possible role of histamine in the development of high-fat diet (HFD)-induced obesity. METHODS: Histamine-deficient histidine decarboxylase knock-out (HDC-KO) mice and C57BL/6J wild-type (WT) mice were given either a standard diet (STD) or HFD for 8 weeks. Body weight, 24-hour caloric intake, epididymal adipose tissue size, plasma leptin concentration and quantitative expression of leptin receptor (Ob-R) mRNA were measured. RESULTS: Both HDC-KO and WT mice fed an HFD for 8 weeks increased their body weight significantly more than STD-fed mice. A significant difference in body weight gain between HDC-KO mice fed an HFD or an STD was seen after 2 weeks, whereas a significant difference in body weight gain was first observed after 5 weeks in WT mice. After 8 weeks 24-hour caloric intake was significantly lower in HFD- than in STD-fed WT mice. In HDC-KO mice no difference in caloric intake was observed between HFD- and STD-fed mice. After 8 weeks epididymal adipose tissue size and plasma leptin concentration had increased significantly in HFD-fed WT and HDC-KO mice compared to their STD-fed controls. Epididymal adipose tissue size was higher in HDC-KO than WT mice, both in STD- and HFD-fed mice. A significant decrease in Ob-R mRNA in HFD-fed HDC-KO mice compared to STD-fed HDC-KO mice was observed, while no such difference was observed in WT mice. CONCLUSION: Based on our results, we conclude that histamine plays a role in the development of HFD-induced obesity.

A role of the histaminergic system for the control of feeding by orexigenic peptides.

A considerable number of neuropeptides are involved in the hypothalamic regulation of feeding behavior. We previously reported that leptin, the ob gene product, expressed its anorectic effect though the histaminergic system via histamine H(1) receptors. However, the interactions among the orexigenic neuropeptides, such as orexin-A, neuropeptide Y (NPY), and ghrelin, and the histaminergic system have not yet been clarified. In this study, we investigated the effect of the neuropeptides on the hypothalamic histamine release in rats, and on food intake and locomotor activity in H(1)-receptor knockout (H1R-KO) mice. Orexin-A increased the histamine release and locomotor activity, but not food intake, suggesting that the histaminergic system participates in arousal rather than feeding by orexin-A. NPY also increased histamine release, but its effect was not immediate. NPY-injected H1R-KO mice consumed more food than the wild-type mice; thus, the histaminergic system may act as a feedback factor downstream of NPY. Ghrelin did not affect histamine release, and it increased food intake, even in H1R-KO mice. Thus, ghrelin expresses its action in a histamine-independent manner.

GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary thromboembolism.

Platelet glycoprotein VI (GPVI) is now considered to be a major player in platelet-collagen adhesive interactions leading to thrombus formation. GPVI blockade, or its depletion, has been shown in mice to result in complete protection against arterial thrombosis, without significant prolongation of bleeding time. GPVI may therefore represent a useful antithrombotic target. In order to reaffirm the role of GPVI in platelet-collagen interactions, we developed GPVI(null) mice by targeted disruption methodology. GPVI(null) mice platelets failed to respond to a high dose of fibrillar collagen, or convulxin, a GPVI agonist, but showed a normal response to other agonists such as ADP, PMA and arachidonic acid. We report, for the first time, that a proportion of GPVI(null) mice is protected against lethal thromboembolism, induced by the infusion of a mixture of collagen and epinephrine. Greater than 55% of GPVI(null) mice survived the challenge, whereas the maximal survival from the other genotypes was 17% (n=18 per genotype). Washed platelets obtained from GPVI(null) mice showed >90% reduction in adhesion to fibrillar collagen under static conditions. Platelet adhesion to collagen under dynamic conditions using a high shear rate (2600 s(-1)) was dramatically reduced using blood from GPVI(null) mice, while platelets from wild-type and heterozygous animals showed a similar amount of adhesion. Animals from each genotype had essentially similar tail bleeding time, suggesting that a complete deficiency of GPVI, at least in mice, does not result in an enhanced bleeding tendency. These observations clearly establish that blockade of GPVI may attenuate platelet-collagen interactions without adversely affecting the bleeding time.

Antioxidant defense of rainbow trout (Oncorhynchus mykiss) in relation to dietary n-3 highly unsaturated fatty acids and vitamin E contents.

This study examined the modulation of the antioxidant status and related physiological changes in rainbow trout Oncorhynchus mykiss under different levels of dietary n-3 highly unsaturated fatty acids (n-3 HUFA) and vitamin E. Six diets containing 0, 100 or 1000 mg alpha-tocopheryl acetate kg(-1) diet and 20% or 48% n-3 HUFA provided by normal fish oil or DHA concentrated fish oil, respectively, were fed to 100 g size fish for 15 weeks. Growth of fish fed vitamin E deficient diets under both levels of n-3 HUFA were slightly retarded, accompanied by a reduction of hematocrit values, an enlargement of liver and spleen, an elevation of lipid hydroperoxide in red blood cell and the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase). Supplementation of vitamin E could protect the fish from these adverse effects; however the higher dose was no better compared to the moderate dose. The modulations were clearly seen in fish fed high n-3 HUFA (48%) since they were under greater oxidative stress as indicated by the markers, lipid hydroperoxide and 8-isoprostane. The increased activity of enzymes corresponds to physiological mechanisms combating the elevation of free radicals under oxidative stress and a dietary fatty acid profile-dependent moderate dose of vitamin E is all that is required to function as an effective antioxidant.

Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity.

Histamine H(1) receptors (H(1)-Rs) are found in peripheral tissues and in regions of the hypothalamus that are concerned with regulating body composition. In the present study, we investigated the detailed mechanisms of histamine H(1)-Rs in the development of obesity. Histamine H(1)-R knockout (H1KO) mice gradually developed mature-onset obesity, which was accompanied by hyperphagia and decreased expression of uncoupling protein-1 (UCP-1) mRNA. Both younger nonobese (12-week-old) and older obese (48-week-old) H1KO mice exhibited impairment of the responsiveness to the leptin. In addition, disruption of the diurnal rhythm of feeding occurred before the onset of obesity in H1KO mice. Correction of these abnormal feeding rhythms by means of scheduled feeding caused a reduction in obesity and associated metabolic disorders in H1KO mice. Furthermore, central administration of a histamine H(1)-R agonist affected feeding behavior, body weight, and c-fos-like immunoreactivity in the hypothalamus. Taken together, these findings suggest that histamine H(1)-Rs are crucial for the regulation of feeding rhythm and in mediating the effects of leptin. Early disruption of H(1)-R-mediated functions in H1KO mice may lead to hyperphagia and decreased expression of UCP-1 mRNA, which may contribute to the development of obesity in these animals. In addition, centrally acting histamine H(1)-R may be a novel therapeutic target for the treatment of obesity and related metabolic disorders.

Association of a four-amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: molecular and functional analysis.

OBJECTIVE: To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cell-specific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay. RESULTS: We identified a glutamic acid-proline-glutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP+ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P = 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P = 0.006). WEHI-231 cells transfected with EPEP+ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP+ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. CONCLUSION: These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.

Evaluation of the effects of anti-pruritic drugs on scratch responses using histamine H1 receptor-deficient mice.

The effects of anti-pruritic drugs on scratching behavior associated with passive cutaneous anaphylaxis in histamine H(1) receptor-deficient and wild-type mice were studied. Passive sensitization with mouse monoclonal anti-dinitrophenyl-immunoglobulin E (IgE) resulted in an increase in the incidence of scratching behavior induced by intravenous injection of dinitrophenyl-ovalbumin in both wild-type and histamine H(1) receptor-deficient mice. The histamine H(1) receptor antagonist diphenhydramine inhibited scratching behavior induced by antigen in passively sensitized wild-type mice, whereas no effect was observed in histamine H(1) receptor-deficient mice. On the other hand, oxatomide inhibited scratching behavior in both mice, although the effect in wild-type mice was more potent than that in histamine H(1) receptor-deficient mice. Tranilast inhibited scratching behavior with the same potency in both mice. We concluded that the scratching behavior associated with passive cutaneous anaphylaxis involves not only histamine H(1) receptors but also other chemical mediators. Furthermore, the results of the present study indicated that oxatomide has an antagonistic effect on histamine H(1) receptors as well as anti-pruritic effect in vivo.

22-Oxacalcitriol prevents progressive glomerulosclerosis without adversely affecting calcium and phosphorus metabolism in subtotally nephrectomized rats.

BACKGROUND: 22-Oxacalcitriol (OCT), an analogue of vitamin D, has been shown to inhibit cell proliferation in cultured mesangial cells. OCT also prevented albuminuria and glomerular injury in an acute model of anti-Thy1 glomerulonephritis. However, potential side effects, including calcaemic actions and tubular dysfunction, of chronic OCT treatment remain unclear. In the present study, we evaluated the effect of OCT in a chronic model of progressive glomerulosclerosis in subtotally nephrectomized (SNX) rats. METHODS: At one week after subtotal nephrectomy, SNX rats were divided into 3 groups having equivalent serum creatinine levels and body weight. OCT (0.08 or 0.4 micro g/kg body weight) was administered intravenously three times per week for 8 weeks to SNX rats. We evaluated effects of OCT on renal function during treatment and on morphologic parameters in glomeruli at 8 weeks. We additionally measured calcium and phosphate levels in serum and urine, and tubular dysfunction markers, including beta(2)-microgloblin (beta(2)m) and N-acetyl-beta-D-glycosaminidase (NAG) levels in urine. RESULTS: OCT treatment significantly suppressed urinary albumin excretion, prevented increases in serum creatinine and serum urea nitrogen, and inhibited glomerular cell number, glomerulosclerosis ratio and glomerular volume in SNX rats at 8 weeks. At that time, OCT-treated groups did not show hypercalcaemia, hypercalciuria or hyperphosphaturia. Furthermore, OCT treatment did not affect beta(2)m or NAG levels in urine, and did not induce histological changes in tubular or interstitial regions. CONCLUSIONS: These findings suggest that OCT may provide a clinically useful agent for preventing the progression of glomerulosclerosis without adversely affecting calcium and phosphorus metabolism or causing subsequent tubular dysfunction.

Effects of long-chain fatty alcohol on peripheral nerve conduction and bladder function in diabetic rats.

Diabetic cystopathy as manifested by an enlarged bladder is mainly caused by peripheral neuropathy. Long-chain fatty alcohol, which has been isolated from the Far-Eastern traditional medicinal plant, Hygrophilia erecta, Hochr., has been found to possess some neurotrophic activities on the central neuron. Cyclohexenonic long-chain fatty alcohol (FA) used in this study were synthesized in order to improve the efficiency of the molecules. The effects of this compound on peripheral nerves, however, have not yet been studied. To get more information, we evaluated the effects of this compound on peripheral nerves in streptozotocin-induced diabetic rats in terms of nerve conduction velocity and bladder function. Three experiments were performed 8 weeks after the administration of streptozotocin to 8-week-old rats: (i) motor sciatic nerve conduction (MNCV), (ii) monitoring micturition behavior in the metabolic cage, and (iii) cystometrogram under urethane anesthesia (CMG). Half of the diabetic rats were treated with FA (8 mg/kg/day, i.p.). The difference in MNCV between control rats (49.0 +/- 2.2 m/s) and untreated diabetic rats (42.4 +/- 0.5 m/s) after 8 weeks reached significance (p = 0.0183). FA-administrated diabetic rats showed an improved MNCV (45.8 +/- 1.2 m/s). We also identified a significant improvement of bladder function in these animals. The diabetic rats had a much higher maximal micturition volume per 24 hours (4.9 +/- 0.4 ml) than control animals (1.5 +/- 0.1 ml). However, the diabetic rats treated with FA had a maximal micturition volume of only 3.7 +/- 0.3 ml. Likewise, the diabetic rats had a CMG bladder capacity of 0.90 +/- 0.14 ml while the diabetic rats treated with FA had a capacity of 0.54 +/- 0.07 ml. These results indicate that cyclohexenonic long-chain fatty alcohol has a beneficial effect on peripheral neuropathy and cystopathy in streptozotocin-induced diabetic rats.