Takayuki Yamamoto

Dual action of isoprenols from herbal medicines on both PPARγ and PPARα in 3T3‐L1 adipocytes and HepG2 hepatocytes

Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator‐activated receptors (PPARs) as determined using the novel GAL4 ligand‐binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARγ but also PPARα as determined using the chimera assay system. These compounds also activated full‐length human PPARγ and PPARα in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARγ and PPARα in 3T3‐L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARγ and PPARα can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.

Overexpression and Ribozyme-mediated Targeting of Transcriptional Coactivators CREB-binding Protein and p300 Revealed Their Indispensable Roles in Adipocyte Differentiation through the Regulation of Peroxisome Proliferator-activated Receptor γ

The cAMP-response element-binding protein-binding protein (CBP) and p300 are common coactivators for several transcriptional factors. It has been reported that both CBP and p300 are significant for the activation of peroxisome proliferator-activated receptor γ (PPARγ), which is a crucial nuclear receptor in adipogenesis. However, it remains unclear whether CBP and/or p300 is physiologically essential to the activation of PPARγ in adipocytes and adipocyte differentiation. In this study, we investigated the physiological significance of CBP/p300 in NIH3T3 cells transiently expressing PPARγ and CBP and in 3T3-L1 preadipocytes stably expressing CBP- or p300-specific ribozymes. In PPARγ-transfected NIH3T3 cells, induction of expression of PPARγ target genes such as adipocyte fatty acid-binding protein (aP2) and lipoprotein lipase (LPL) by adding thiazolidinedione was enhanced, depending on the amount of a CBP expression plasmid transfected. Expression of aP2 and LPL genes, as well as glycerol-3-phosphate dehydrogenase activity and triacylglyceride accumulation after adipogenic induction, was largely suppressed in 3T3-L1 adipocytes expressing either the CBP- or p300-specific active ribozyme, but not in inactive ribozyme-expressing cells. These data suggest that both CBP and p300 are indispensable for the full activation of PPARγ and adipocyte differentiation and that CBP and p300 do not mutually complement in the process.

Abietic acid activates peroxisome proliferator-activated receptor-γ (PPARγ) in RAW264.7 macrophages and 3T3-L1 adipocytes to regulate gene expression involved in inflammation and lipid metabolism

Abietic acid is one of the terpenoids, which are multifunctional natural compounds. It has been reported that abietic acid suppresses effects on inflammation. However, the mechanism underlying the anti‐inflammatory effects remains unclear. The present work indicates that abietic acid suppresses the protein expression of tumor necrosis factor‐α and cyclooxygenase 2, which are involved in inflammation, in lipopolysaccharide‐stimulated macrophages. Moreover, this effect resembles that of thiazolidinedione, a synthetic peroxisome proliferator‐activated receptor‐γ (PPARγ) ligand. Indeed, abietic acid activates PPARγ in luciferase reporter assays. The activity of abietic acid induces PPARγ target gene expression in RAW264.7 macrophages and 3T3‐L1 adipocytes. These data indicate that abietic acid is a PPARγ ligand and that its anti‐inflammatory effect is partly due to the activation of PPARγ in stimulated macrophages. The present work suggests a novel possibility that abietic acid, a naturally occurring compound, can be used not only for anti‐inflammation but also for regulating lipid metabolism and atherosclerosis.

Effects of caffeine on the uncoupling protein family in obese yellow KK mice.

1.u2002The hypothesis that caffeine upregulates uncoupling protein (UCP)‐1, UCP‐2 and UCP‐3 expression, which contribute to thermogenesis, was investigated in obese mice.

Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis

BACKGROUND & AIMSnIndigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC.nnnMETHODSnWe performed a multicenter, double-blind trial evaluating the safety of 86 patients in Japan with active UC (Mayo scores of 6 or more), enrolled from March 30 through December 27, 2016. Patients were randomly assigned to groups and given a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was the rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1xa0point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1. The main secondary endpoint was the rate of clinical remission at week 8, defined as a Mayo score or ≤2 and no subscores with axa0value >1. Mucosal healing was also assessed at weekxa08.nnnRESULTSnThe trial was terminated because of an external reason: a report of pulmonary arterial hypertension in a patient who used self-purchased IN for 6xa0months. In the intent-to-treat analysis, we observed a significant, dose-dependent linear trend in proportions of patients with clinical responses (13.6% with a clinical response to placebo; 69.6% to 0.5 g IN; 75.0% to 1.0xa0g IN; and 81.0% to 2.0 gxa0IN) (Cochran-Armitage trend test Pxa0<xa0.0001 compared with placebo). Proportions of patients in clinical remission at week 8 were significantly higher in the 1.0 g IN group (55.0%, Pxa0=xa0.0004) and the 2.0 g IN group (38.1%, (Pxa0=xa0.0093) than in the placebo group (4.5%). Proportions of patients with mucosal healing were 13.6% in the placebo group, 56.5% in the 0.5 g IN group, 60.0% in the 1.0 g IN group, and 47.6% inxa0the 2.0 g IN group (P = .0278 compared with placebo). Although mild liver dysfunction was observed in 10 patients who received IN, no serious adverse events were observed.nnnCONCLUSIONSnIn a randomized, placebo-controlled trial, wexa0found 8 weeks of IN (0.5-2.0 g per day) to be effective inxa0inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adversexa0effects, including pulmonary arterial hypertension. Clinical Trials Registry no: UMIN000021439 (http://www.umin.ac.jp/ctr/).

Time-of-Flight Magnetic Resonance Angiography With Sparse Undersampling and Iterative Reconstruction: Comparison With Conventional Parallel Imaging for Accelerated Imaging.

ObjectivesThe aim of this study was to evaluate the clinical feasibility of accelerated time-of-flight (TOF) magnetic resonance angiography with sparse undersampling and iterative reconstruction (sparse TOF). Materials and MethodsThe local institutional review board approved the study protocols. Twenty healthy volunteers were recruited (mean age, 31.2 years; age range, 22-52 years; 14 men, 6 women). Both sparse TOF and parallel imaging (PI) TOF were obtained on a 3 T scanner. Acceleration factors were 3, 4, 5, 6, and 8 for sparse TOF (Sp 3×, Sp 4×, Sp 5×, Sp 6×, and Sp 8×, respectively) and 2, 3, 4, and 6 for PI TOF (PI 2×, PI 3×, PI 4×, and PI 6×, respectively). Images were reconstructed on the scanner, and maximum intensity projection images were subjected to visual evaluation, wherein each segment of the major brain arteries was independently evaluated by 2 radiologists on a 4-point scale (1, poor; 2, limited; 3, moderate/good quality for diagnosis; and 4, excellent). As a quantitative evaluation, the apparent contrast-to-background deviation (apparent CBD) was calculated at the level of the basilar artery and the pons. ResultsA total number of 1800 segments were subjectively evaluated. There was substantial agreement regarding vessel visualization (&kgr; = 0.759). Sparse TOF received scores above 3 (good for diagnosis) at any acceleration factor up to the third segments of major arteries. The middle and distal segments of PI 4× and PI 6× were graded below 3 (limited or poor diagnostic value). Sp 3×, 4×, 5×, and 6× retained diagnostic information (graded above 3), even at distal segments. The apparent CBD of sparse TOF at any acceleration factor was equivalent to that of PI 2×, whereas the apparent CBD of PI 3×, PI 4×, and PI 6× attenuated with the acceleration factor. ConclusionsSparse TOF can achieve better image quality relative to PI TOF at higher acceleration factors. The diagnostic quality of distal branches (A2/3, M4, P4) was maintained with Sp 6×, which achieved a shorter acquisition time less than half of PI 2×.

Carbon tetrachloride-induced hepatic and renal damages in rat: inhibitory effects of cacao polyphenol

Here, we investigated the protective effect of cacao polyphenol extract (CPE) on carbon tetrachloride (CCl4)-induced hepato-renal oxidative stress in rats. Rats were administered CPE for 7 days and then received intraperitoneal injection of CCl4. Two hours after injection, we found that CCl4 treatment significantly increased biochemical injury markers, lipid peroxides (phosphatidylcholine hydroperoxide (PCOOH) and malondialdehyde (MDA)) and decreased glutathione peroxidase activity in kidney rather than liver, suggesting that kidney is more vulnerable to oxidative stress under the present experimental conditions. CPE supplementation significantly reduced these changes, indicating that this compound has antioxidant properties against CCl4-induced oxidative stress. An inhibitory effect of CPE on CCl4-induced CYP2E1 mRNA degradation may provide an explanation for CPE antioxidant property. Together, these results provide quantitative evidence of the in vivo antioxidant properties of CPE, especially in terms of PCOOH and MDA levels in the kidneys of CCl4-treated rats. Graphical abstract Rats were supplemented with CPE prior to CCl4 treatment. CCl4 significantly increased PCOOH and MDA in kidney rather than liver, and CPE significantly ameliorated these damages.

An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn’s disease

BackgroundGranulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn’s disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD.MethodsIn an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level).ResultsOf the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 ± 5.3 days in the weekly GMA and 21.7 ± 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/μL to 6950/μL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern.ConclusionsIn this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.

Piceatannol exhibits anti-inflammatory effects on macrophages interacting with adipocytes

Abstract Piceatannol (PIC), a natural analog of resveratrol (RES), is a phytochemical found in passion fruit seeds. To clarify the effects of PIC on obesity‐induced inflammation in adipose tissue, we investigated the anti‐inflammatory activity of PIC‐related compounds (PIC, RES, and metabolites from PIC) in culture models of obese adipose tissue. Lipopolysaccharide (LPS) and conditioned medium from 3T3‐L1 adipocytes (3T3‐L1‐CM) enhanced proinflammatory gene expression and synthesis of nitric oxide (NO), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) in RAW264.7 macrophages. Although each compound inhibited the mRNA expression of iNOS (inducible NO synthase), TNF‐α, and IL‐6, PIC potently inhibited them, and 30 μmol/L PIC suppressed the LPS‐ and 3T3‐L1‐CM‐induced mRNA expression of iNOS (70.4% and 69.2% suppression, respectively), TNF‐α (42.6% and 47.0% suppression), and IL‐6 (27.3% and 42.1% suppression). PIC also significantly suppressed production of NO (80.3% suppression) and inflammatory cytokines (TNF‐α; 33.7% suppression, IL‐6; 66.5% suppression). Furthermore, PIC was found to rescue the uncoupling protein 1 mRNA expression induced by isoproterenol in 10T1/2 adipocytes, which was suppressed by LPS‐activated macrophages. These results suggest that PIC may attenuate the pathologic inflammation triggered by adipose tissues.

An Increased Serum N-Terminal Telopeptide of Type I Collagen, a Biochemical Marker of Increased Bone Resorption, Is Associated with Infliximab Therapy in Patients with Crohn’s Disease

AbstractBackgroundOsteopenia and osteoporosis are considered to be extra-intestinal manifestations of inflammatory bowel disease (IBD). Anti-tumor necrosis factor (TNF)-α biologics have been introduced as novel medications for an active IBD. However, it is still not well documented whether anti-TNF-α affects the frequency of bone loss or abnormality of bone mineral markers among patients with IBD.AimsThis study was to investigate the biochemical basis of low bone mineral density (BMD) and increased turnover in IBD during infliximab (IFX) therapy.MethodsnForty patients with Crohn’s disease (CD), 80 patients with ulcerative colitis (UC), and 65 age- and gender-matched controls were included. BMD was measured with dual-energy X-ray absorptiometry, and vitamins K and D were measured as serum undercarboxylated osteocalcin (ucOC) and 1,25-(OH)2D, respectively. Bone formation and resorption were based on measuring bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), respectively.ResultsSignificantly lower BMD was found in patients with UC and CD as compared to controls (Pxa0<xa00.05). BAP, 1,25-(OH)2D, ucOC, and NTx were significantly higher in CD patients, but not in UC patients as compared to controls (Pxa0<xa00.05). Further, serum NTx level was significantly higher in CD patients who were receiving IFX as compared to CD patients who were not receiving IFX (Pxa0<xa00.01).ConclusionsA lower BMD and higher bone metabolism markers were found in CD patients as compared to controls or UC patients. A significant increased serum level of NTx, a biochemical marker of increased bone resorption, was observed in CD patients during IFX therapy.