Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) results from amyloid-ß deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer's disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-ß removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-ß through suppressing the ApoE-ERK1/2-amyloid-ß precursor protein axis, despite the low permeability of the blood-brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-ß production and beneficially modulating proinflammatory microglial phenotypes.

Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways.

Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD+ level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and -unrelated pathways.

Colloidal submicron-particle curcumin exhibits high absorption efficiency-a double-blind, 3-way crossover study.

Curcumin is a major constituent of the spice turmeric and has various biological activities, including anticancer, antioxidant, and anti-inflammatory properties, as well as alcohol detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to exert its bioactivities. To overcome this problem, several curcumin preparations with a drug-delivery system (DDS) have been developed to increase the bioavailability of curcumin after oral administration, and tested as functional foods and potential medical agents in humans. We have also produced capsules containing Theracurmin, curcumin dispersed with colloidal submicron-particles. To evaluate the absorption efficiency of three types of DDS curcumin, we performed a double-blind, 3-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin and 2 other capsule types of curcumin with DDS, BCM-95 (micronized curcumin with turmeric essential oils) and Meriva (curcumin-phospholipid). Nine healthy subjects (male/female=5/4, age: 24-32 y old) were administered these 3 preparations of DDS curcumin, at commonly used dosages. Six capsules of Theracurmin, 1 capsule of BCM-95, and 2 capsules of Meriva contain 182.4 ± 1.0, 279.3 ± 10.7, and 152.5 ± 20.3 mg of curcumin, respectively. The maximal plasma curcumin concentration (0-24 h) of Theracurmin was 10.7 to 5.6 times higher than those of BCM-95 and Meriva, respectively. Moreover, the area under the blood concentration-time curve at 0-24 h was found to be 11.0- and 4.6-fold higher with Theracurmin than BCM-95 and Meriva, respectively. These data indicate that Theracurmin exhibits a much higher absorption efficiency than other curcumin DDS preparations.

Effects of natural S-equol supplements on overweight or obesity and metabolic syndrome in the Japanese, based on sex and equol status.

OBJECTIVES: Epidemiologic studies indicate that soy intake has an important role in the prevention of age-related health problems. Daidzein, the principal isoflavone contained in soy, is converted to S-equol by the intestinal bacteria. Not all individuals, however, can produce S-equol, which is considered the most biologically active metabolite. We studied the effects of a natural S-equol supplement on metabolic parameters associated with overweight or obesity and metabolic syndrome. METHODS: The study was a randomized, double-blinded, placebo-controlled, crossover design with no washout period. All subjects were considered overweight or obese if they had a body mass index ≥ 25 kg/m(2) . Placebo or natural S-equol tablets containing 10 mg S-equol were orally ingested each day for 12 weeks. A total of 54 Japanese overweight or obese outpatients were enrolled. The equol phenotype was determined, and various metabolic parameters, including cardio-ankle vascular index (CAVI), were measured. RESULTS: Equol non-producers comprised 67.9% of the overweight or obese subjects. The ratio of equol non-producers in this overweight or obese subject group was higher than the previously reported ratio of equol non-producers (approximately 50%) in the general population. Compared with the placebo group, intervention with natural S-equol led to a significant decrease in HbA1c, serum low-density lipoprotein cholesterol (LDL-C) levels and CAVI score. Furthermore, the effect was more prominent in the subgroup of female equol non-producers. CONCLUSION: The ratio of equol non-producers in overweight or obese populations might be higher than generally reported. Natural S-equol might have a role in glycaemic control and in the prevention of cardiovascular disease by its effects to lower LDL-C levels and CAVI scores in overweight or obese individuals.

A novel drug delivery system of oral curcumin markedly improves efficacy of treatment for heart failure after myocardial infarction in rats.

Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with the deterioration of heart failure. We reported that native curcumin, at a dosage of 50 mg/kg, prevented deterioration of the systolic function in rat models of heart failure. To achieve more efficient oral pharmacological therapy against heart failure by curcumin, we have developed a novel drug delivery system (DDS) which markedly increases plasma curcumin levels. At the dosage of 0.5 mg/kg, DDS curcumin but not native curcumin restored left ventricular fractional shortening in post-myocardial infarction rats. Thus, our DDS strategy will be applicable to the clinical setting in humans.

Is there an undiscovered neurocircuit for regulating GH secretion? -Pitfalls of GHRP-2 and ITT as GH provocative tests-.

GH secretion is mainly regulated at the hypothalamus by a dual interplay between growth hormone releasing hormone (GHRH) and somatostatin, which are modulated by various factors. We examined the regulatory mechanism of GH secretion in an apparently healthy young man without decreased IGF-1 concentration and nocturnal GH secretion, but who showed low responses to insulin tolerance (ITT) and to GHRP-2 tests. The patient also had no GH response to acute aerobic exercise. However, he had normal secretion of pituitary hormone based on hypothalamic releasing hormone tests combined with CRH, GRH as GHRH, LH-RH and TRH. In addition, he had a GH response without paradoxical secretion to TRH stimulation as well as an ACTH response to subcutaneous glucagon stimulation, and AVP secretion responded to 5% hypertonic saline infusion, though it was not adequately stimulated by ITT. MRI showed no structural abnormalities in the hypothalamus-pituitary gland. These findings indicate that this subject may have an undiscovered neurocircuit for regulating GH secretion, as well as other neurohormones, to maintain homeostasis, even though there were low responses of the hormones to ITT and GHRP-2 stimuli, probably via altered secretion of hypothalamic hormones.

Metabolic effects of 20-kilodalton human growth hormone (20K-hGH) for adults with growth hormone deficiency: results of an exploratory uncontrolled multicenter clinical trial of 20K-hGH.

The biological effects of 20-kDa human GH (20K-hGH), which is produced in the pituitary by alternative splicing of GH mRNA and comprises approximately 6% of all GH in serum, have not been reported. We have investigated the metabolic effects of recombinant 20K-hGH in adult patients with GH deficiency in an exploratory study. Three doses of 20K-hGH (0.006, 0.012, and 0.024 mg/kg.d), were administered for 16 wk to three groups (consisting of 18 or 19 subjects), respectively. The 20K-hGH dose-dependently increased serum IGF-I and IGFBP-3 levels, and the lowest dose (0.006 mg/kg) was enough to normalize both hormones by wk 4. Serum osteocalcin levels and urinary deoxypyridinoline excretion were also dose-dependently increased. There was a significant decrease in body fat mass with an increase of lean body mass at the lowest dose of 0.006 mg/kg.d. Blood glucose and serum insulin were increased significantly at 4 wk only in the high-dose group (0.024 mg/kg). Glucose tolerance was slightly impaired in 26-39% of patients in all treatment groups as judged by oral glucose tolerance tests, but there was no development of overt diabetes. The major adverse event in the 20K-hGH treatment was peripheral edema, similar to the incidence reported for 22K-hGH. The data demonstrated that 20K-hGH had metabolic effects comparable to those of 22K-hGH in humans. The results suggest that 20K-hGH could be used to treat GH-deficient patients, although further studies may be required to investigate the optimum dose and superiority of 20K-hGH over 22K-hGH in a comparative study.

Adiponectin in anorexia nervosa and bulimia nervosa.

To study the role of adiponectin, a novel adipocyte-specific secreted protein, on the pathophysiology of eating disorders, circulating levels of fasting adiponectin, leptin, insulin, and glucose were measured in 31 female patients with anorexia nervosa (AN) and in 11 with bulimia nervosa. Hormone levels were compared with 16 age-matched, normal body weight controls, six healthy constitutionally thin subjects, and nine obese subjects. Moreover, changes in levels were reevaluated after nutritional treatment and weight gain in 13 patients with AN. Serum adiponectin concentrations in AN and bulimia nervosa were significantly lower than those in normal-weight controls. These results were unexpected because the levels were high in constitutionally thin subjects and low in obese subjects, which provide a negative correlation with body mass index (BMI) and body fat mass. In contrast, serum leptin levels correlated very well with BMI and fat mass among all the patients and controls. The insulin resistance was significantly low in AN and high in obese subjects. The concentrations of adiponectin after weight recovery increased to the normal level despite a relatively small increase in BMI. These findings suggest that abnormal feeding behavior in the patients with eating disorders may reduce circulating adiponectin level, and weight recovery can restore it.