Na Rang Moon

Yuzu Extract Prevents Cognitive Decline and Impaired Glucose Homeostasis in β-Amyloid–Infused Rats

Our preliminary study revealed that dementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis (unpublished). We therefore evaluated whether long-term oral consumption of yuzu (Citrus junos Tanaka) extract improves cognitive dysfunction and glucose homeostasis in β-amyloid-induced rats. Male rats received hippocampal CA1 infusions of β-amyloid (25-35) [plaque forming β-amyloid; Alzheimer disease (AD)] or β-amyloid (35-25) [non-plaque forming β-amyloid; C (non-Alzheimer disease control)] at a rate of 3.6 nmol/d for 14 d. AD rats were divided into 2 dietary groups that received either 3% lyophilized 70% ethanol extracts of yuzu (AD-Y) or 3% dextrin (AD-C) in high-fat diets (43% energy as fat). The AD-C group exhibited greater hippocampal β-amyloid deposition, which was not detected in the C group, and attenuated hippocampal insulin signaling. Yuzu treatment prevented β-amyloid accumulation, increased tau phosphorylation, and attenuated hippocampal insulin signaling observed in AD-C rats. Consistent with β-amyloid accumulation, the AD-C rats experienced cognitive dysfunction, which was prevented by yuzu. AD-C rats gained less weight than did C rats due to decreased feed consumption, and yuzu treatment prevented the decrease in feed consumption. Serum glucose concentrations were higher in AD-C than in C rats at 40-120 min after glucose loading during an oral-glucose-tolerance test, but not at 0-40 min. Serum insulin concentrations were highly elevated in AD-C rats but not enough to lower serum glucose to normal concentrations, indicating that rats in the AD-C group had insulin resistance and a borderline diabetic state. Although AD-C rats were profoundly insulin resistant, AD-Y rats exhibited normal first and second phases of glucose tolerance and insulin sensitivity and secretion. In conclusion, yuzu treatment prevented the cognitive dysfunction and impaired energy and glucose homeostasis induced by β-amyloid infusion.

Central visfatin potentiates glucose-stimulated insulin secretion and β-cell mass without increasing serum visfatin levels in diabetic rats.

INTRODUCTION Our previous study revealed that plasma visfatin levels were lower in pregnant women with gestational diabetes (GDM) than non-GDM independent of prepreganacy BMI. We examined whether central visfatin modulates energy and glucose homeostasis via altering insulin resistance, insulin secretion or islet morphometry in diabetic rats. METHODS Partial pancreatectomized, type 2 diabetic, rats were interacerbroventricularly infused with visfatin (100ng/rat/day, Px-VIS), visfatin+visfatin antagonist, CHS-828 (100μg/rat/day, Px-VIS-ANT), or saline (control, Px-Saline) via osmotic pump, respectively, for 4weeks. RESULTS Central visfatin improved insulin signaling (pAkt→pFOXO-1) but not pSTAT3 in the hypothalamus. Central visfatin did not alter serum visfatin levels in diabetic rats whereas the levels were higher in non-diabetic rats than diabetic rats. Body weight at the 2nd week was lowered in the Px-VIS group due to decreased food intake in the first two weeks compared to the Px-Saline group and energy expenditure was not significantly different among the treatment groups of diabetic rats. Visfatin antagonist treatment nullified the central visfatin effect. Px-VIS increased whole body glucose disposal rates in euglycemic hyperinsulinemic clamp compared to Px-Saline and lowered hepatic glucose output, whereas Px-VIS-ANT blocked the visfatin effect on insulin resistance (P<0.05). In hyperglycemic clamp study, the area under the curve of insulin in first and second phase were significantly higher in the Px-VIS group than the Px-Saline group without modifying insulin sensitivity at the hyperglycemic state, whereas the increase in serum insulin levels was blocked in the Px-VIS-ANT group. Central visfatin also increased β-cell mass by increasing β-cell proliferation. CONCLUSIONS Central visfatin improved glucose homeostasis by increasing insulin secretion and insulin sensitivity at euglycemia through the hypothalamus in diabetic rats. Therefore, visfatin is a positive modulator of glucose homeostasis by delivering the hypothalamic signals into the peripheries.

β-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing β-cell mass in non-diabetic and diabetic rats

OBJECTIVE β-Amyloid accumulation in the brain may impair glucose homeostasis in both the brain and peripheral tissues. The present study investigated whether β-amyloid deposition in the hippocampus impairs glucose homeostasis by altering insulin sensitivity, glucose-stimulated insulin secretion or β-cell mass. METHODS Male rats were divided into two groups: a non-diabetic sham group and a diabetic partial pancreatectomized (Px) group. Each group was then subdivided into three treatment groups that received intra-CA1 infusions of β-amyloid (25-35; AMY), β-amyloid (35-25; RAMY; non-plaque forming), or saline at a rate of 3.6 nmol/day for 14 days. RESULTS After 4weeks, cognitive function measured by passive avoidance and water maze tests was impaired in non-diabetic rats that received AMY compared with rats that received saline or RAMY. Furthermore, diabetes exacerbated cognitive dysfunction in AMY-infused rats. This was associated with the hyperphosphorylation of tau as a result of attenuated insulin signaling (pAkt→pGSK) through decreased phosphorylation of cAMP responding element binding protein in the hippocampus of non-diabetic and diabetic rats. AMY exacerbated whole-body and hepatic insulin resistance in non-diabetic and diabetic rats. However, AMY potentiated glucose-stimulated insulin secretion in non-diabetic and diabetic rats, but caused decreased β-cell mass via increased β-cell apoptosis and decreased β-cell proliferation. As a result, glucose homeostasis was maintained by potentiating insulin secretion in diabetic rats, but may not be sustainable with further decreases in β-cell mass. CONCLUSION Cognitive dysfunction attributable to β-amyloid accumulation in the hippocampus might be related to disturbed glucose homeostasis due to increased insulin resistance and decreased β-cell mass.

Central acylated ghrelin improves memory function and hippocampal AMPK activation and partly reverses the impairment of energy and glucose metabolism in rats infused with β-amyloid

Ghrelin is a gastric hormone released during the fasting state that targets the hypothalamus where it induces hunger; however, emerging evidence suggests it may also affect memory function. We examined the effect of central acylated-ghrelin and DES-acetylated ghrelin (native ghrelin) on memory function and glucose metabolism in an experimentally induced Alzheimers disease (AD) rat model. AD rats were divided into 3 groups and Non-AD rats were used as a normal-control group. Each rat in the AD groups had intracerebroventricular (ICV) infusion of β-amyloid (25-35; 16.8nmol/day) into the lateral ventricle for 3 days, and then the pumps were changed to infuse either acylated-ghrelin (0.2nmol/h; AD-G), DES-acylated ghrelin (0.2nmol/h; AD-DES-G), or saline (control; AD-C) for 3 weeks. The Non-AD group had ICV infusion of β-amyloid (35-25) which does not deposit in the hippocampus. During the next 3 weeks memory function, food intake, body weight gain, body fat composition, and glucose metabolism were measured. AD-C exhibited greater β-amyloid deposition compared to Non-AD-C, and AD-G suppressed the increased β-amyloid deposition and potentiated the phosphorylation AMPK. In addition, AD-G increased the phosphorylation GSK and decreased the phosphorylation of Tau in comparison to AD-C and AD-DES-G. Cognitive function, measured by passive avoidance and water maze tests, was much lower in AD-C than Non-AD-C whereas AD-G but not AD-DES-G prevented the decrease (p<0.021). Body weight gain was lower in AD-C group than Non-AD-C group without changing epididymal fat mass. AD-G reversed the decrease in body weight which was due to increased energy intake and decreased energy expenditure. The AD-G group exhibited a decrease in the second part of serum glucose levels during an oral glucose tolerance test (OGTT) compared to the AD-C and AD-DES-G group (p<0.009). However, area under the curve of insulin during the first part of OGTT was higher in AD-DES-G than other groups, whereas during the second part it was suppressed in AD-G as much as Non-AD. In conclusion, central acylated ghrelin in rats prevented the deterioration of memory function, and energy and glucose metabolisms were partially improved, possibly due to less β-amyloid accumulation. This research suggests that interventions such as intermittent fasting to facilitate sustained elevations of acyl-ghrelin should be investigated for cognitive and metabolic benefits, especially in person with early symptoms of memory impairment.

The supplementation of Korean mistletoe water extracts reduces hot flushes, dyslipidemia, hepatic steatosis, and muscle loss in ovariectomized rats

Since Korean mistletoe (Viscum album) has been used for alleviating metabolic diseases, it may also prevent the impairment of energy, glucose, lipid, and bone metabolisms in an estrogen-deficient animal model. We determined that long-term consumption of Korean mistletoe water extract (KME) can alleviate menopausal symptoms such as hot flush, increased abdominal fat mass, dyslipidemia, hyperglycemia, and decreased bone mineral density in ovariectomized (OVX) rats fed a high-fat diet, and explored the mechanisms of the effects. OVX rats were divided into four groups and fed high-fat diets supplemented with either 0.6% dextrin (control), 0.2% lyophilized KME + 0.4% dextrin (KME-L), or 0.6% lyophilized KME (KME-H). Sham rats were fed with the high-fat diets with 0.6% dextrin as a normal-control without estrogen deficiency. After eight weeks, OVX rats exhibited impaired energy, glucose and lipid metabolism, and decreased uterine and bone masses. KME-L did not alleviate energy dysfunction. However, KME-H lowered serum levels of total-, LDL-cholesterol, and triglycerides and elevated serum HDL-cholesterol levels in OVX rats with dyslipidemia, to similar levels as normal-control rats. Furthermore, KME-H improved HOMA-IR, an indicator of insulin resistance, in OVX rats. Surprisingly, KME-H fed rats had greater lean mass in the abdomen and leg without differences in fat mass but neither dosage of KME altered bone mineral density in the lumbar spine and femur. The increased lean mass was related to greater phosphorylation of mTOR and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in the quadriceps muscles. Hepatic triglyceride contents were lowered with KME-H in OVX rats by increasing carnitine palmitoyltransferase-1 (CPT-1) expression and decreasing fatty acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c) expression. In conclusion, KME may be useful for preventing some menopausal symptoms such as hot flushes, dyslipidemia, hepatic steatosis, and loss of muscle mass in post-menopausal women.

Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and β-cell survival in gerbils

Abstract Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimers disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimers disease.

Topical treatments of Saussurea costus root and Thuja orientalis L. synergistically alleviate atopic dermatitis-like skin lesions by inhibiting protease-activated receptor-2 and NF-κB signaling in HaCaT cells and Nc/Nga mice

ETHNOPHARMACOLOGICAL RELEVANCE The root of Saussurea costus (Aucklandia lappa Decne, Aucklandiae Radix, SC) and Thuja orientalis L. (TOL) have been traditionally used as anti-inflammatory agents in Korea. However, they have not been studied for the efficacy of atopic dermatitis (AD) treatment, a chronic inflammatory skin disease. We investigated the efficacy of topical applications with 1,3-butyleneglycol extracts of SC and TOL to alleviate the symptoms of AD. MATERIALS AND METHODS HaCaT cells and the dorsal skin of Nc/Nga mice had a local exposure of house mite extracts and 2,4-dinitrochlorobenzene (DNCB), respectively. After lesions developed, we topically applied 1,3-butylen glycol (vehicle; control), SC (30%), TOL (30%), or SC (15%)+TOL (15%) to the skin lesions for 5 weeks. The normal-control was not exposed to DNCB. The skin thickness, mast cell infiltration, serum immunoglobulin E (IgE) and IgG1 and gene expressions of interleukin (IL)-4, IL-13, and IFN-γ in the dorsal skin and HaCaT cells were measured. RESULTS Chlorogenic acid (129.6±10.2μg/g) for SC and catechin and apigenin (93.4±13.2 and 16.9±1.3μg/g, respectively) for TOL were used as indicator compounds for the strength of the extracts. SC+TOL decreased the expression of protease-activated receptor-2 and ICAM-1 and the release of TNF-α and IL-6 in HaCaT cells activated by 3μg/mL house mite extracts in comparison to either of SC or TOL alone. In Nc/Nga mice challenged with DNCB, SC+TOL synergistically attenuated clinical symptoms of AD such as erythema, hemorrhage, edema, excoriation and dryness in the dorsal skin better than either SC or TOL alone. Histological analysis of the dorsal skin also showed that SC+TOL treatment significantly and additively decreased the inflammatory cellular infiltrate, including mast cells and eosinophils in comparison to either of SC or TOL. SC+TOL also decreased serum IgE and IgG1 levels and the expression of IFN-γ, IL-4, and IL-13 mRNA in dorsal skin in DNCB-treated Nc/Nga mice. CONCLUSION SC+TOL relieved the symptoms of AD by reducing pro-inflammatory activity and over-activated immune responses. These data suggest that SC+TOL may be an effective alternative intervention for the management of AD.

Consumption of ellagic acid and dihydromyricetin synergistically protects against UV-B induced photoaging, possibly by activating both TGF-β1 and wnt signaling pathways

Ellagic acid (EGA) and dihydromyricetin (DHM) are both found in fruits and vegetables are used for anti-aging treatment for the skin. The anti-photoaging efficacy of EGA and DHM was investigated in UV-B irradiated skin in vivo and the involvement of transforming growth factor (TGF)-β1 and wnt signaling pathways were examined in vitro. HaCaT cells were treated with either 50μM EGA, 50μM DHM or 25μM EGA+25μM DHM before 100mJ/cm2 UV-B exposure, and then oxidative stress and inflammation was measured. The involvement of TGF-β1 and wnt signaling was measured using their inhibitors, respectively, in HaCaT cells. Mice were fed a high fat diet with either 0.7% cellulose, 0.7% EGA, 0.7% DHM or 0.35% EGA+0.35% DHM for 3weeks and the dorsal skin of the mice had UV-B irradiation. 3% cellulose, 3% EGA, 3% DHM or 1.5% EGA+1.5% DHM in 1,3-buthylene glycol was applied onto the dorsal skin at 30min before 1 MED UV-B exposure. In 100mJ/cm2 UVB irradiation, EGA and DHM mainly decreased oxidative stress and inflammation, respectively in HaCaT cells. Their activities were blocked by the TGF-β1 inhibitor, indicating their actions were mediated by TGF-β1 signaling (TGF-β1➔pSmad3➔Smad7). DHM enhanced wnt signaling by increasing β-catenin and decreasing Dickkopf-related protein-1. In mice, 1 MED UV-B exposure induced sunburn, redness, and blistering. EGA, DHM and especially EGA+DHM lessened their severity. UV-B increased epidermal thickness and damaged epidermal nucleus and cell structures. DHM and especially EGA+DHM prevented damage to the nucleus and cell structures. Expressions of circulating and dorsal skin IL-1β and TNF-α mRNA were lower in descending order of: control, EGA, DHM, EGA+DHM and normal-control. In conclusion, the consumption of EGA+DHM had a synergistically protective action against UV-B damage in the skin tissues of mice and HaCaT cells, and it may be associated with activating of both TGF-β1 and wnt signaling.