[Show abstract][Hide abstract] ABSTRACT: We investigated whether a highly purified eicosapentaenoic acid (EPA) and a concentrated n-
3 fatty acid formulation (prescription TAK-085) containing EPA and docosahexaenoic acid (DHA) ethyl
ester improve the learning ability of aged rats and whether this specific outcome has any relation with
the brain levels of EPA-derived eicosanoids and DHA-derived docosanoids. The rats were tested for
reference memory errors (RMEs) and working memory errors (WMEs) in an eight-arm radial maze.
Fatty acid compositions were analyzed by GC, whereas brain eicosanoid/docosanoids were measured
by LC-ESI-MS-MS-based analysis. The levels of lipid peroxides (LPOs) were measured by thiobarbituric
acid reactive substances. Compared with the control rats, the administration of TAK-085 at 300
mg*kg−1day−1 for 17 weeks reduced the number of RMEs in aged rats. Both TAK-085 and EPA
administration increased plasma EPA and DHA levels in aged rats, with concurrent increases in DHA
and decreases in arachidonic acid in the corticohippocampal brain tissues. TAK-085 administration
significantly increased the formation of EPA-derived 5-HETE and DHA-derived 7-, 10-, and 17-HDoHE,
PD1, RvD1, and RvD2. ARA-derived PGE2, PGD2, and PGF2α significantly decreased in TAK-085-
treated rats. DHA-derived mediators demonstrated a significantly negative correlation with the
number of RMEs, whereas EPA-derived mediators did not exhibit any relationship. Furthermore,
compared with the control rats, the levels of LPO in the plasma, cerebral cortex, and hippocampus
were significantly reduced in TAK-085-treated rats. The findings of the present study suggest that
long-term EPA+DHA administration may be a possible preventative strategy against age-related
BBA - Molecular and Cell Biology of Lipids. 10/2014;
[Show abstract][Hide abstract] ABSTRACT: Alzheimer’s disease (AD) is characterized by brain deposition of amyloid β (Aβ) fibers, leading to neurodegeneration and impairments of memory. Effective medication for AD is still an elusive. Here, we investigated the effects of madecassoside (MD), an active triterpenoid in Centella asiatica, on in vitro Aβ1-42 fibrillation and Aβ1-42-induced toxicity in SH-SY5Y cells and memory impairment in Aβ1-42-infused Alzheimer’s disease (AD) model rats in vivo. MD significantly inhibited the Aβ1-42 fibril formation, as indicated by thioflavin-T fluorometry, laser scanning microscopy and transmission electron microscopy. Co-treatment with MD significantly attenuated Aβ1-42-induced apoptosis in SH-SY5Y cells. The AD rat model displayed a significant loss of spatial memory, which was significantly improved with oral preadministration of MD. MD also decreased the brain Aβ1-42 burden, oxidative stress, TNF and cathepsin D levels, with concomitant increases in BDNF and PSD-95 levels in the hippocampus. Our data indicate that MD may provide therapeutic benefits in AD.
International Journal of Indigenous Medicinal Plants. 09/2014; 47(2):1669-1682.
[Show abstract][Hide abstract] ABSTRACT: Long-term continuous exposure to high ambient temperatures induces complete heat acclimation in humans and animals. However, to date, the effects of long-term exposure to heat stress on cells have not been fully evaluated. In this study, we investigated an adaptive physiological process induced in culture cells by continuous exposure to mild heat stress for 60 days. The results of this investigation provide evidence that after long-term heat acclimation in cells, (1) heat shock protein levels are increased, (2) hypoxia inducible factor-1α (HIF-1α) expression is upregulated, and (3) heat shock-induced and hypoxia-induced apoptoses are attenuated. These results suggest that the hypoxia response pathway is an intrinsic part of the heat acclimation repertoire and that the HIF-1 pathway following long-term heat acclimation induces cells with cross tolerance against hypoxia.
Cell biochemistry and biophysics 03/2014; · 3.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Arachidonic acid (20:4n-6, ARA) is a major component of the cell membrane, whereas ARA-derived eicosanoids are formed when cells are damaged. Aging is associated with an accretion of oxidative stress in skeletal muscles. In this study, we examined the effects of chronic administration (13 weeks) of ARA (240 mg/kg/day) on fatty acid composition, antioxidative status, and morphology of slow (soleus muscles) and fast (extensor digitorum longus muscles; EDL)-twitch muscles in aged rats (21 months old). The level of reactive oxygen species was higher in the EDL of ARA-administered rats than in that of control rats. ARA administration decreased the muscle cell volumes and increased the number of slow myosin heavy chain (MHC)-positive cells in the EDL. The relative content of MHC2X was increased whereas the relative content of MHC2B was decreased in the EDL of ARA-administered rats. These results suggest that ARA deposition in the fast-twitch muscle of aged rats reduced cell volume with an increase in oxidative stress.
Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA). 01/2014;
[Show abstract][Hide abstract] ABSTRACT: The omega-3 polyunsaturated fatty acids (ω-3 PUFAs) docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA) protect against diabetic nephropathy by inhibiting inflammation. The aim of this study was to assess the effects of highly purified DHA and EPA or EPA only administration on renal function and renal eicosanoid and docosanoid levels in an animal model of metabolic syndrome, SHR.Cg-Leprcp/NDmcr (SHRcp) rats. Male SHRcp rats were divided into 3 groups. Control (5% arabic gum), TAK-085 (300 mg/kg/day, containing 467 mg/g EPA and 365 mg/g DHA), or EPA (300 mg/kg/day) was orally administered for 20 weeks. The urinary albumin to creatinine ratio in the TAK-085-administered group was significantly lower than that in other groups. The glomerular sclerosis score in the TAK-085-administered group was significantly lower than that in the other groups. Although DHA levels were increased in total kidney fatty acids, the levels of nonesterified DHA were not significantly different among the 3 groups, whereas the levels of protectin D1, resolvin D1, and resolvin D2 were significantly increased in the TAK-085-administered group. The results show that the use of combination therapy with DHA and EPA in SHRcp rats improved or prevented renal failure associate with metabolic syndrome with decreasing triglyceride levels and increasing ω-3 PUFA lipid mediators.
[Show abstract][Hide abstract] ABSTRACT: Metabolic syndrome is implicated in the decline of cognitive ability. We investigated whether the prescription n-3 fatty acid administration improves cognitive learning ability in SHR.Cg-Lepr (cp) /NDmcr (SHR-cp) rats, a metabolic syndrome model, in comparison with administration of eicosapentaenoic acid (EPA, C20:5, n-3) alone. Administration of TAK-085 [highly purified and concentrated n-3 fatty acid formulation containing EPA ethyl ester and docosahexaenoic acid (DHA, C22:6, n-3) ethyl ester] at 300 mg/kg body weight per day for 13 weeks reduced the number of reference memory-related errors in SHR-cp rats, but EPA alone had no effect, suggesting that long-term TAK-085 administration improves cognitive learning ability in a rat model of metabolic syndrome. However, the working memory-related errors were not affected in either of the rat groups. TAK-085 and EPA administration increased plasma EPA and DHA levels of SHR-cp rats, associating with an increase in EPA and DHA in the cerebral cortex. The TAK-085 administration decreased the lipid peroxide levels and reactive oxygen species in the cerebral cortex and hippocampus of SHR-cp rats, suggesting that TAK-085 increases antioxidative defenses. Its administration also increased the brain-derived neurotrophic factor levels in the cortical and hippocampal tissues of TAK-085-administered rats. The present study suggests that long-term TAK-085 administration is a possible therapeutic strategy for protecting against metabolic syndrome-induced learning decline.
Neurochemical Research 08/2013; · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is known that aquaporin (AQP) 5 expression in the apical membrane of acinar cells in salivary glands is important for the secretion of saliva in rodents and humans. Although heat acclimation enhances saliva secretion in rodents, the molecular mechanism of how heat induces saliva secretion has not been determined. Here, we found that heat acclimation enhanced the expression of AQP5 and AQP1 in rat submandibular glands concomitant with the promotion of the HIF-1α pathway, leading to VEGF induction and CD31-positive angiogenesis. The apical membrane distribution of AQP5 in serous acinar cells enhanced after heat acclimation, while AQP1 expression was restricted to the endothelial cells in the submandibular glands. A network of AQPs may be involved in heat-acclimated regulation in saliva secretion. Because AQPs probably plays a crucial role in saliva secretion in humans, these findings may lead to a novel strategy for treating saliva hyposecretion.
[Show abstract][Hide abstract] ABSTRACT: Polyunsaturated fatty acids (PUFAs) can induce neurogenesis and recovery from brain diseases. However, the exact mechanisms of the beneficial effects of PUFAs have not been conclusively described. We recently reported that docosahexaenoic acid (DHA) induced neuronal differentiation by decreasing Hes1 expression and increasing p27(kip1) expression, which causes cell cycle arrest in neural stem cells (NSCs). In the present study, we examined the effect of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on differentiation, expression of basic helix-loop-helix transcription factors (Hes1, Hes6, and NeuroD), and the cell cycle of cultured NSCs. EPA also increased mRNA levels of Hes1, an inhibitor of neuronal differentiation, Hes6, an inhibitor of Hes1, NeuroD, and Map2 mRNA and Tuj-1-positive cells (a neuronal marker), indicating that EPA induced neuronal differentiation. EPA increased the mRNA levels of p21(cip1) and p27(kip1), a cyclin-dependent kinase inhibitor, which indicated that EPA induced cell cycle arrest. Treatment with AA decreased Hes1 mRNA but did not affect NeuroD and Map2 mRNA levels. Furthermore, AA did not affect the number of Tuj-1-positive cells or cell cycle progression. These results indicated that EPA could be involved in neuronal differentiation by mechanisms alternative to those of DHA, whereas AA did not affect neuronal differentiation in NSCs.
[Show abstract][Hide abstract] ABSTRACT: Natural killer (NK) cells have many functional activities, including cytotoxicity and the capacity to produce cytokines and chemokines. NK cell activity is regulated partly by eicosanoids, which are produced from arachidonic acid (ARA) and eicosapentaenoic (EPA) acid. In this study, we investigated the effects of long-term therapy with ARA or docosahexaenoic acid (DHA) on the cytotoxic effects of the NK cells of young rats, which were fed on a nonfish oil diet for two generations. Control oil, ARA (240 mg/kg BW/day) or DHA (240 mg/kg BW/day) were orally administrated to the rats for 13 weeks before determining the cytotoxic activity of NK cells from the spleen against YAC-1 mouse lymphoma cell line, as well as the plasma levels of docosanoids or eicosanoids and inflammatory cytokines. Long-term ARA administration significantly suppressed the cytotoxic activity of NK cells. Moreover, ARA administration significantly increased the plasma levels of ARA, prostaglandin (PG) E2, and PGD2. However, DHA administration did not produce any different effects compared with those in the control rats. Furthermore, the inflammatory cytokine levels were not affected by the administration of ARA or DHA. These results suggest that long-term ARA administration has an inhibitory effect on the tumor cytotoxicity of NK cells in rat spleen lymphocytes owing to the enhanced synthesis of PGE2 and PGD2 from ARA because of the elevated plasma ARA levels in young rats.
[Show abstract][Hide abstract] ABSTRACT: Reactive oxygen species (ROS) production induced by α,β-dicarbonyl compounds and advanced glycation end products causes renal dysfunction in patients with type 2 diabetes and metabolic syndrome. Hydrogen-rich water (HRW) increases the H2 level in blood and tissues, thus reducing oxidative stress in animals as well as humans. In this study, we investigated the effects of HRW on glucose- and α,β-dicarbonyl compound-induced ROS generation in vitro and in vivo.
Kidney homogenates from Wistar rats were incubated in vitro with glucose and α,β-dicarbonyl compounds containing HRW, following which ROS levels were measured. In vivo animal models of metabolic syndrome, SHR.Cg-Leprcp/NDmcr rats, were treated with HRW for 16 weeks, following which renal ROS production and plasma and renal α,β-dicarbonyl compound levels were measured by liquid chromatograph mass spectrometer.
HRW inhibited glucose- and α,β-dicarbonyl compound-induced ROS production in kidney homogenates from Wistar rats in vitro. Furthermore, SHR.Cg-Leprcp/NDmcr rats treated with HRW showed a 34% decrease in ROS production. Moreover, their renal glyoxal, methylglyoxal, and 3-deoxyglucosone levels decreased by 81%, 77%, and 60%, respectively. Positive correlations were found between renal ROS levels and renal glyoxal (r = 0.659, p = 0.008) and methylglyoxal (r = 0.782, p = 0.001) levels.
These results indicate that HRW inhibits the production of α,β-dicarbonyl compounds and ROS in the kidneys of SHR.Cg-Leprcp/NDmcr rats. Therefore, it has therapeutic potential for renal dysfunction in patient with type 2 diabetes and metabolic syndrome.
[Show abstract][Hide abstract] ABSTRACT: To investigate the effect of acute heat stress on the day-night circadian gene Per2 mRNA expression in the liver of rats.
Male Wistar rats were randomly divided into two groups and exposed to heat at 32 degrees celsius; or to a room temperature at 24 degrees celsius; (control). After 7 days of heat exposure, the body temperature was measured by telemetry. The relative weight of the pituitary and adrenal glands was determined after the exposure, and liver Per2 mRNA expression level was detected using RT-PCR.
Acute heat stress did not obviously affect body temperature or body weight of the rats. Seven days of heat exposure increased the relative weight of the pituitary and adrenal glands and significantly lowered Per2 mRNA expression level at night.
Acute heat stress can interfere with the day-night circadian gene Per2 mRNA expression in rats.
Nan fang yi ke da xue xue bao = Journal of Southern Medical University 02/2012; 32(2):215-7.
[Show abstract][Hide abstract] ABSTRACT: The heat shock response has been extensively studied by a number of investigators to understand the molecular mechanism underlying the cellular response to severe heat stress (higher than 42°C). But, body or tissue temperature increases by only a few degrees Celsius during physiological events. Therefore, the physiological cellular response to mild heat stress rather than severe heat stress is likely to be more important. Repeated exposure to hyperthermia for consecutive 5 days induces heat acclimation which is an adaptive physiological process in humans and animals. However, thus far, the effect of continuous exposure to heat stress on cells has not been fully evaluated. In this study, we investigated an adaptive physiological process that is induced in culture cells by continuous exposure to mild heat stress for 5 days. Exposure to heat activated p38-mitogen-activated protein kinase; inhibited cell growth without apoptosis; and increased the levels of HSPs and HSF-1 in mouse fibroblast cells. Interestingly, exposure to heat regulated the expression of aquaporins and induced morphological change. In a physiological sense, these results suggested that continuous exposure to mild heat stress for 5 days, in which heat acclimation is attained in humans and animals, might induce molecular adaptation to heat in cells.
Cellular Physiology and Biochemistry 01/2012; 30(2):450-7. · 3.42 Impact Factor