Taurine increases hippocampal neurogenesis in aging mice.

Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.

Stem Cell Res . 2015 May; 14(3): 369-379.

Comparison between single and combined post-treatment with S-Methyl-N,N-diethylthiolcarbamate sulfoxide and taurine following transient focal cerebral ischemia in rat brain.

We have recently reported on the efficacy of an N-methyl-d-aspartate (NMDA) receptor partial antagonist, S-Methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), in improving outcome following stroke, including reduced infarct size and calcium influx, suppressing the endoplasmic reticulum (ER) stress-induced apoptosis as well as improving behavioral outcome. DETC-MeSO was shown to suppress the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, one of the major ER stress pathways. Several studies including ours have provided evidence that taurine also has neuroprotective effects through reducing apoptosis and inhibiting activating transcription factor 6 (ATF6) and inositol requiring enzyme 1 (IRE-1) pathways. We hypothesized that a combined treatment with DETC-MeSO and taurine would ameliorate ischemia-induced brain injury by inhibiting all three ER stress pathways. Twenty four hours following reperfusion of a 2-h ischemic stroke, rats received either 0.56-mg/kg DETC-MeSO or 40-mg/kg of taurine, either alone or in combination, subcutaneously for 4days. Our study showed that combined DETC-MeSO and taurine, but not DETC-MeSO alone at the dose used, greatly reduced the infarct size, improved performance on the neuro-score test and attenuated proteolysis of alphaII-spectrin. Meanwhile, the level of the pro-apoptotic protein, Bax, declined and the anti-apoptotic protein, B-cell lymphoma 2 (BCL-2), expression was markedly increased. Combination therapy decreased both caspase-12 and caspase-3 activation by preventing the release of Cytochrome-c from mitochondria, indicating attenuation of apoptosis in ischemic infarct. Glucose-regulated protein (GRP)78 as a marker of the unfolded protein response decreased and levels of the key ER stress protein markers p-PERK-ATF4, p-eIF2alpha and cleaved-ATF-6 were found to significantly decline. NeuN expression levels indicated that more neurons were protected in the presence of DETC-MeSO and taurine. We also showed that combined treatment can prevent gliosis and increase p-AKT a pro-survival marker in the penumbra. Therefore, we conclude that combined treatment with both DETC-MeSO and taurine synergistically inhibits all three ER stress pathways and apoptosis and therefore can be a novel and effective treatment after ischemic stroke.

Neuroscience . 2015 Aug 6; 300: 460-473.

Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment.

The aim of this paper is to provide a comprehensive review of the epidemiological evidence linking type 2 diabetes mellitus and its related conditions, including obesity, hyperinsulinemia, and metabolic syndrome, to Alzheimer’s disease (AD). Several mechanisms could help to explain this proposed link; however, our focus is on insulin resistance and deficiency. Studies have shown that insulin resistance and deficiency can interact with amyloid-beta protein and tau protein phosphorylation, each leading to the onset and development of AD. Based on those epidemiological data and basic research, it was recently proposed that AD can be considered as “type 3 diabetes”. Special attention has been paid to determining whether antidiabetic agents might be effective in treating AD. There has been much research both experimental and clinical on this topic. We mainly discuss the clinical trials on insulin, metformin, thiazolidinediones, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors in the treatment of AD. Although the results of these trials seem to be contradictory, this approach is also full of promise. It is worth mentioning that the therapeutic effects of these drugs are influenced by the apolipoprotein E (APOE)-epsilon4 genotype. Patients without the APOE-epsilon4 allele showed better treatment effects than those with this allele.

Clin Interv Aging. 2015 10: 549-560.

Gradual lesion expansion and brain shrinkage years after stroke.

BACKGROUND AND PURPOSE: Lesioned brains of patients with stroke may change through the course of recovery; however, little is known about their evolution in the chronic phase. Here, we aimed to quantify the extent of lesion volume change and brain atrophy in the chronic poststroke brain using magnetic resonance imaging. METHODS: Optimized T1-weighted scans were collected more than once (time between visits=2 months to 6 years) in 56 patients (age=36-90 years; time poststroke=3 months to 20 years). Volumetric changes attributable to lesion growth and atrophy were quantified with automated procedures. We looked at how volumetric changes related to time between visits, using nonparametric statistics, after controlling for age, time poststroke, and brain and lesion size at the earlier time. RESULTS: Lesions expanded more in patients who had longer time-intervals between their imaging sessions (partial rank correlation rho=0.56; P<0.001). The median rate of lesion growth was 1.59 cm(3) per year. Across patients, the whole-brain atrophy rate was 0.95% per year, with accelerated atrophy in the ipsilesional hemisphere. CONCLUSIONS: We show gradual lesion expansion many years after stroke, beyond that expected by normal aging and after controlling for other variables. Future studies need to understand how structural reorganization enables long-term recovery even when the brain is shrinking.

Stroke. 2014 Mar; 45(3): 877-879.

Cooperation of taurine uptake and dopamine D1 receptor activation facilitates the induction of protein synthesis-dependent late LTP.

Co-activation of NMDA and dopamine receptors is required for the induction of the late phase of LTP (L-LTP) that is dependent on new protein synthesis. Other neuromodulatory substances may also contribute to this process. Here, we examined whether taurine is one of the neuromodulators contributing to L-LTP induction, since it is known that taurine uptake induces a long-lasting synaptic potentiation dependent on protein synthesis, and taurine uptake inhibition blocks L-LTP induced by tetanization. Experiments were conducted using rat hippocampal slices where field synaptic potentials were evoked and recorded in CA3-CA1 synapses. Taurine (1 mM) applied 10 min before a high frequency stimulation (HFS) train converted a transitory early-LTP (E-LTP) into an L-LTP dependent on protein synthesis. This taurine effect was blocked by a taurine uptake inhibitor. A facilitation of L-LTP induction was also obtained by pre-application of SKF38393, a D1/D5 dopamine receptor (D1R) agonist. In this case, LTP facilitation was not affected by the taurine uptake inhibitor. Nevertheless, when taurine and SKF38393 were simultaneously pre-applied at a concentration that individually did not modify E-LTP, they produced a synergistic mechanism that facilitated the induction of L-LTP with a sole HFS train. This facilitation of L-LTP was blocked by inhibiting either taurine uptake or D1R activation. Taurine and SKF38393 activated different signaling pathways to transform E-LTP into L-LTP. Taurine-induced L-LTP facilitation required MAPK activation, while D1R-agonist-induced facilitation depended mainly on PKA activation and partially on MAPK activation. On the other hand, the synergistic mechanisms induced by the cooperative action of taurine and SKF38393 were impaired by inhibitors against MAPK, PKA and PI3-K. This pharmacological profile resembles that displayed by L-LTP induced by three HFS trains at 10-min intervals. These results indicate that taurine uptake is necessary and cooperates with other neurotransmitter systems in the induction of L-LTP.

Neuropharmacology. 2014 Apr; 79: 101-111.

Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism.

AIMS: Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies, lack of correlation with the bioavailable concentrations is a critical issue. Some reports had suggested that these molecules downregulate the stress response, which may affect growth and the antioxidant protection of malignant cells. Initially, we studied this potential underlying mechanism using different human melanomas (with genetic backgrounds correlating with most melanomas), growing in nude mice as xenografts, and pterostilbene (Pter, a natural dimethoxylated analog of resveratrol). RESULTS: Intravenous administration of Pter decreased human melanoma growth in vivo. However, Pter, at levels measured within the tumors, did not affect melanoma growth in vitro. Pter inhibited pituitary production of the adrenocorticotropin hormone (ACTH), decreased plasma levels of corticosterone, and thereby downregulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent antioxidant defense system in growing melanomas. Exogenous corticosterone or genetically induced Nrf2 overexpression in melanoma cells prevented the inhibition of tumor growth and decreased antioxidant defenses in these malignant cells. These effects and mechanisms were also found in mice bearing different human pancreatic cancers. Glutathione depletion (selected as an antimelanoma strategy) facilitated the complete elimination by chemotherapy of melanoma cells isolated from mice treated with Pter. INNOVATION: Although bioavailability-related limitations may preclude direct anticancer effects in vivo, natural polyphenols may also interfere with the growth and defense of cancer cells by downregulating the pituitary gland-dependent ACTH synthesis. CONCLUSIONS: Pter downregulates glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells.

Antioxid Redox Signal. 2016 Jun 10; 24(17): 974-990.

Imaging of cellular aging in human retinal blood vessels.

To date two main aging vascular lesions have been reported in elderly human retinas: acellular capillaries and microaneurysms. However, their exact mechanism of formation remains unclear. Using high resolution microscopy techniques we revise cellular alterations observed in aged human retinal vessels, such as lipofuscin accumulation, caveolae malfunction, blood basement membrane disruption and enhanced apoptosis that could trigger the development of these aging vascular lesions. Moreover, we have generated a set of original images comparing retinal vasculature between middle and old aged healthy humans to show in a comprehensive manner the main structural and ultrastructural alterations occurred during age in retinal blood vessels.

Exp Eye Res. 2015 Jun; 135: 14-25.

Blueberry treatment decreased D-galactose-induced oxidative stress and brain damage in rats.

D-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of whole fresh blueberry (BB) (Vaccinium corymbosum L.) treatment on oxidative stress in age-related brain damage model. Rats received GAL (300 mg/kg; s.c.; 5 days per week) alone or together with 5 % (BB1) and 10 % (BB2) BB containing chow for two months. Malondialdehyde (MDA),protein carbonyl (PC) and glutathione (GSH) levels, and Cu Zn-superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione transferase (GST) activities as well as acetylcholinesterase (AChE) activities were determined. Expressions of B cell lymphoma-2 (Bcl-2), Bax and caspase-3 were also evaluated in the brain by immunohistochemistry. MDA and PC levels and AChE activity increased, but GSH levels, SOD and GSH-Px activities decreased together with histopathological structural damage in the brain of GAL-treated rats. BB treatments, especially BB2 reduced MDA and PC levels and AChE activity and elevated GSH levels and GSH-Px activity. BB1 and BB2 treatments diminished apoptosis and ameliorated histopathological findings in the brain of GAL-treated rats. These results indicate that BB partially prevented the shift towards an imbalanced prooxidative status and apoptosis together with histopathological amelioration by acting as an antioxidant (radical scavenger) itself in GAL-treated rats.

Metab Brain Dis. 2015 Jun; 30(3): 793-802.

ERK5/HDAC5-mediated, resveratrol-, and pterostilbene-induced expression of MnSOD in human endothelial cells.

SCOPE: Mitochondrial oxidative stress is closely correlated with numerous cardiovascular diseases. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme in mitochondria. Although polyphenols can induce the expression of MnSOD, their corresponding mechanisms remains unclear. In this study, we tested the hypothesis that resveratrol and pterostilbene can activate the expression of MnSOD through an AMPK-ERK5/HDAC5-KLF2 pathway. METHODS AND RESULTS: Our results revealed that two stilbenes reduced mitochondrial superoxide-free radicals, and endothelial cell senescence, and increased the mRNA expression of several genes related to mitochondrial function, including MnSOD. Moreover, two stilbenes upregulated the activation of human MnSOD promoter luciferase reporter gene and protein level in human umbilical vein endothelial cells. Similarly, two stilbenes also stimulated LKB1, AMPKalpha, extracellular-signal related kinase 5 (ERK5) phosphorylation, and histone acetylase 5 (HDAC5) and Kruppel-like factor 2 (KLF2) expression. The knockdown of AMP-activated protein kinase (AMPK), ERK5, and HDAC5 by using short-hairpin RNA blocked pterostilbene-induced phosphorylation of their downstream signaling proteins and the expression of KLF2. Furthermore, using a chromatin immunoprecipitation-PCR detection method, we found that resveratrol and pterostilbene promoted KLF2 binding to CACCC sites of the human MnSOD promoter. CONCLUSION: Resveratrol and pterostilbene can activate MnSOD expression through ERK5/HDAC5 pathway, thus alleviating mitochondrial oxidative stress in endothelial cells that relates to cardiovascular disease.

Mol Nutr Food Res. 2016 Feb; 60(2): 266-277.

Restoration of sirt1 function by pterostilbene attenuates hypoxia-reoxygenation injury in cardiomyocytes.

Restoration of blood supply to ischemic myocardium causes cardiomyocyte damage, a process known as ischemia-reperfusion injury. Excess reactive oxygen species and intracellular calcium contribute to cell damage but the involvement of sirt1, a versatile protein deacetylase in reperfusion-induced cell damage remains unknown. Here, we found that hypoxia-reoxygenation, an in vitro model of ischemia-reperfusion injury, induced H9c2 cardiomyocyte apoptosis as revealed by caspase-3 assay, Hoechst 33258 staining, flow cytometric analysis and JC-1 staining. Molecular docking analysis showed that, pterostilbene, a natural dimethyl ether derivative of resveratrol, binds to the enzymatic active pocket of sirt1. Importantly, application of pterostilbene at low concentrations of 0.1-3.0 muM rescued H9c2 cells from apoptosis, an effect comparable with resveratrol at 20 muM. Mechanistically, pterostilbene exerted its cardioprotective effects via 1) stimulation of sirt1 activity, since pretreatment of H9c2 cells with splitomicin, an antagonist of sirt1, removed the effects of pterostilbene, and 2) enhancement of sirt1 expression. Therefore, the present study demonstrates that activation of sitr1 during ischemia-reperfusion is cardioprotective and that the natural compound-pterostilbene-could be used therapeutically to alleviate ischemia-reperfusion injury.

Eur J Pharmacol. 2016 Apr 5; 776: 26-33.

Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRT1 and DNMT enzyme expression, including SIRT1-dependent gamma-H2AX and telomerase regulation in triple-negative breast cancer.

BACKGROUND: Nutrition is believed to be a primary contributor in regulating gene expression by affecting epigenetic pathways such as DNA methylation and histone modification. Resveratrol and pterostilbene are phytoalexins produced by plants as part of their defense system. These two bioactive compounds when used alone have been shown to alter genetic and epigenetic profiles of tumor cells, but the concentrations employed in various studies often far exceed physiologically achievable doses. Triple-negative breast cancer (TNBC) is an often fatal condition that may be prevented or treated through novel dietary-based approaches. METHODS: HCC1806 and MDA-MB-157 breast cancer cells were used as TNBC cell lines in this study. MCF10A cells were used as control breast epithelial cells to determine the safety of this dietary regimen. CompuSyn software was used to determine the combination index (CI) for drug combinations. RESULTS: Combinatorial resveratrol and pterostilbene administered at close to physiologically relevant doses resulted in synergistic (CI <1) growth inhibition of TNBCs. SIRT1, a type III histone deacetylase (HDAC), was down-regulated in response to this combinatorial treatment. We further explored the effects of this novel combinatorial approach on DNA damage response by monitoring gamma-H2AX and telomerase expression. With combination of these two compounds there was a significant decrease in these two proteins which might further resulted in significant growth inhibition, apoptosis and cell cycle arrest in HCC1806 and MDA-MB-157 breast cancer cells, while there was no significant effect on cellular viability, colony forming potential, morphology or apoptosis in control MCF10A breast epithelial cells. SIRT1 knockdown reproduced the effects of combinatorial resveratrol and pterostilbene-induced SIRT1 down-regulation through inhibition of both telomerase activity and gamma-H2AX expression in HCC1806 breast cancer cells. As a part of the repair mechanisms and role of SIRT1 in recruiting DNMTs, the effects of this combination treatment was also explored on DNA methyltransferases (DNMTs) expression. Interestingly, the compounds resulted in a significant down-regulation of DNMT enzymes with no significant effects on DNMT enzyme expression in MCF10A control cells. CONCLUSION: Collectively, these results provide new insights into the epigenetic mechanisms of a novel combinatorial nutrient control strategy that exhibits synergy and may contribute to future recalcitrant TNBC prevention and/or therapy.

BMC Cancer. 2015 15: 672.

A Novel Combinatorial Epigenetic Therapy Using Resveratrol and Pterostilbene for Restoring Estrogen Receptor-alpha (ERalpha) Expression in ERalpha-Negative Breast Cancer Cells.

Breast cancer is the second most common cancer and a leading cause of cancer death in women. Specifically, estrogen receptor-alpha (ERalpha)-negative breast cancers are clinically more aggressive and normally do not respond to conventional hormone-directed therapies such as tamoxifen. Although epigenetic-based therapies such as 5-aza-2’-deoxycytidine and/or trichostatin A as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, respectively, can regulate the expression of ERalpha, this can often lead to a number of side effects. Plant-based dietary compounds such as resveratrol and pterostilbene in novel combinatorial therapy provides new avenues to target these side effects and provide similar results with a higher level of safety. Here, we report that combinatorial resveratrol and pterostilbene leads to the reactivation of ERalpha expression in ERalpha-negative breast cancer cells in a time-dependent manner. Chromatin immunoprecipitation analysis of the ERalpha promoter in each cell type revealed an increase in enrichment of acetyl-H3, acetyl-H3lysine9 (H3K9) and acetyl-H4 active chromatin markers in the ERalpha promoter region after combinatorial treatment. This treatment also resulted in a significant change in HDAC and histone acetyl transferase (HAT) enzyme activity in these cells after 3 days of treatments. The combination resulted in a significant decrease in DNMT enzyme activity and 5-methylcytosine levels in MDA-MB-157 breast cancer cells. Moreover, reactivation of ERalpha expression by resveratrol combined with pterostilbene was found to sensitize ERalpha-dependent response to 17beta-estradiol (E2)-mediated cellular proliferation and antagonist 4-hydroxytamoxifen (4-OHT)-mediated inhibition of cellular proliferation in ERalpha-negative breast cancer cells. E2 and 4-OHT further affected the ERalpha-responsive downstream progesterone receptor (PGR) gene in ERalpha reactivated MDA-MB-157 cells. Collectively, our findings provide a new and safer way of restoring ERalpha expression by regulating epigenetic mechanisms with the use of phytochemicals in combinatorial therapy. This combination can further provide effective treatment options for hormonal refractory breast cancer with available anti-hormonal therapy.

PLoS One. 2016 11(5): e0155057.

Effects of Intravenous and Oral Magnesium on Reducing Migraine: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Migraine attack has been associated with magnesium deficiency. Previous studies investigating the effect of intravenous and oral magnesium on acute migraine attacks and the prevention of migraine have produced equivocal findings. OBJECTIVE: To evaluate the effects of intravenous magnesium on acute migraine attacks and oral magnesium supplements on migraine prophylaxis. STUDY DESIGN: A meta-analysis of randomized controlled trials (RCTs). Electronic databases, namely EMBASE, PubMed, the Wanfang Data Chinese Database, and the China Knowledge Resource Integrated Database were searched from inception to February 24, 2015. METHODS: This review was conducted according to the guidelines of the PRISMA. Only RCTs evaluating the effects of intravenous or oral magnesium on migraine compared with a control group were included. RESULTS: A total of 21 studies were included. Of which, 11 studies investigated the effects of intravenous magnesium on acute migraine (948 participants) and 10 examined the effects of oral magnesium on migraine prophylaxis (789 participants). Intravenous magnesium significantly relieved acute migraine within 15 - 45 minutes, 120 minutes, and 24 hours after the initial infusion (Odd ratios [ORs] = 0.23, 0.20, and 0.25, respectively). Oral magnesium significantly alleviated the frequency and intensity of migraine (ORs = 0.20 and 0.27). LIMITATIONS: Some of the included studies did not adopt adequate randomization methods. CONCLUSIONS: Intravenous magnesium reduces acute migraine attacks within 15 - 45 minutes, 120 minutes, and 24 hours after the initial infusion and oral magnesium alleviates the frequency and intensity of migraine. Intravenous and oral magnesium should be adapted as parts of multimodal approach to reduce migraine.

Pain Physician. 2016 Jan; 19(1): E97-112.

Comparative angioprotective effects of magnesium compounds.

Magnesium (Mg) deficiency is implicated in the development of numerous disorders of the cardiovascular system. Moreover, the data regarding the efficacy of different magnesium compounds in the correction of impaired functions due to low magnesium intake are often fragmentary and inconsistent. The aim of this study was to compare the effects of the most bioavailable Mg compounds (Mg l-aspartate, Mg N-acetyltaurate, Mg chloride, Mg sulphate and Mg oxybutyrate) on systemic inflammation and endothelial dysfunction in rats fed a low Mg diet for 74 days. A low Mg diet decreased the Mg concentration in the plasma and erythrocytes, which was accompanied by a reduced concentration of eNOs and increased levels of endothelin-1 level in the serum and impaired endothelium-dependent vasodilatation. These effects increased the concentration of proinflammatory molecules, such as VCAM-1, TNF-alpha, IL-6 and CRP, indicating the development of systemic inflammation and endothelial dysfunction. The increased total NO level, which estimated from the sum of the nitrate and nitrite concentrations in the serum, may also be considered to be a proinflammatory marker. Two weeks of Mg supplementation partially or fully normalised the ability of the vascular wall to effect adequate endothelium-dependent vasodilatation and reversed the levels of most endothelial dysfunction and inflammatory markers (except CRP) to the mean values of the control group. Mg sulphate had the smallest effect on the endothelin-1, TNF-alpha and VCAM-1 levels. Mg N-acetyltaurate was significantly more effective in restoring the level of eNOS compared to all other studied compounds, except for Mg oxybutyrate. Taken together, the present findings demonstrate that all Mg compounds equally alleviate endothelial dysfunction and inflammation caused by Mg deficiency. Mg sulphate tended to be the least effective compound.

J Trace Elem Med Biol. 2015 Jan; 29: 227-234.

Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring.

OBJECTIVE: Maternal chorioamnionitis is associated with newborn neurologic injury. Recent evidence suggests that maternal administration of magnesium sulphate (MG) may protect fetuses from white matter injury. Previously we demonstrated evidence by magnetic resonance imaging that MG may prevent maternal inflammation-induced gray matter injury of offspring. Thus, we sought to determine the potential of maternal inflammation to induce fetal neurological/behavioral deficits and assess whether maternal MG attenuates these effects. STUDY DESIGN: Pregnant rats at day 18 received injections of intraperitoneal lipopolysaccharide (LPS) or saline. Dams were treated with subcutaneous saline/MG (270 mg/kg followed by 27 mg/kg every 20 minutes) for 2 hours before and following LPS/saline injections. Pups were delivered spontaneously. At 1 and 3 months of age, 11-12 offspring of each group (saline, LPS, MG, LPS-MG) underwent a 2-way shuttle box avoidance testing. The shuttle box is divided in half and the animal moves between compartments to avoid an electric shock in response to an auditory stimulus. RESULTS: Control offspring demonstrated significantly improved learning and memory abilities from age 1 to 3 months. At 1 month, LPS-treated dams’ offspring were similar to controls with no improvement in learning abilities at 3 months. MG treatment of LPS dams significantly improved offspring learning at 3 months, to equal or better than that of controls. CONCLUSION: LPS-stimulated inflammation during pregnancy impairs offspring learning ability and memory, which is ameliorated by maternal MG treatment. These results suggest that maternal MG therapy may prevent white and gray matter injuries associated with maternal infection/inflammation.

Am J Obstet Gynecol. 2015 Dec; 213(6): 851 e851-858.

Low serum magnesium is associated with coronary artery calcification in a Korean population at low risk for cardiovascular disease.

BACKGROUND AND AIMS: Previous studies suggested an association between low serum magnesium levels and metabolic or cardiovascular disease. Additionally, several studies have shown that low serum magnesium is associated with vascular calcification, but there are no studies exploring its relation to coronary artery calcification (CAC). We investigated the relationship between low serum magnesium and CAC by using health examination data. METHODS AND RESULTS: We cross-sectionally analyzed 34,553 participants who underwent coronary multi-detector computed tomography and serum magnesium level measurement in 2010-2012 as part of a health examination program at a tertiary hospital in Korea. CAC was defined as a coronary artery calcium score > 100. Participants were divided into three groups according to their serum magnesium level as follows: low < 1.9 mg/dL (n = 931), normal = 1.9-2.3 mg/dL (n = 32,341), and high > 2.3 mg/dL (n = 1281). The percentages of participants with CAC were 3.7, 1.5, and 2.3 in each group, respectively. According to multivariate analysis, low serum magnesium was associated with CAC after adjustment for age, sex, BMI, diabetes, hypertension, cardiovascular disease, systolic BP, LDL cholesterol, HDL cholesterol, eGFR, serum calcium and phosphorus, hsCRP, current smoking status, alcohol intake and vigorous exercise frequency. The odds ratio for CAC in the low serum magnesium group compared to the normal group was 2.10 (1.40-3.15, P < 0.001). CONCLUSION: Low serum magnesium level is associated with CAC in a Korean population at low risk for cardiovascular disease. Further studies are needed to generalize this finding and to verify the causal relationship between low serum magnesium and CAC.

Nutr Metab Cardiovasc Dis. 2015 Nov; 25(11): 1056-1061.

A review of the effect of diet on cardiovascular calcification.

Cardiovascular (CV) calcification is known as sub-clinical atherosclerosis and is recognised as a predictor of CV events and mortality. As yet there is no treatment for CV calcification and conventional CV risk factors are not consistently correlated, leaving clinicians uncertain as to optimum management for these patients. For this reason, a review of studies investigating diet and serum levels of macro- and micronutrients was carried out. Although there were few human studies of macronutrients, nevertheless transfats and simple sugars should be avoided, while long chain omega-3 fats from oily fish may be protective. Among the micronutrients, an intake of 800 mug/day calcium was beneficial in those without renal disease or hyperparathyroidism, while inorganic phosphorus from food preservatives and colas may induce calcification. A high intake of magnesium (>/=380 mg/day) and phylloquinone (500 mug/day) proved protective, as did a serum 25(OH)D concentration of >/=75 nmol/L. Although oxidative damage appears to be a cause of CV calcification, the antioxidant vitamins proved to be largely ineffective, while supplementation of alpha-tocopherol may induce calcification. Nevertheless other antioxidant compounds (epigallocatechin gallate from green tea and resveratrol from red wine) were protective. Finally, a homocysteine concentration >12 micromol/L was predictive of CV calcification, although a plasma folate concentration of >39.4 nmol/L could both lower homocysteine and protect against calcification. In terms of a dietary programme, these recommendations indicate avoiding sugar and the transfats and preservatives found in processed foods and drinks and adopting a diet high in oily fish and vegetables. The micronutrients magnesium and vitamin K may be worthy of further investigation as a treatment option for CV calcification.

Int J Mol Sci. 2015 16(4): 8861-8883.

Serum Magnesium Status in Patients Subjects with Depression in the City of Yazd in Iran 2013-2014.

Depression is the most common mental disorder and involves many factors. The regulatory effects of magnesium on N-methyl-D-aspartate (NMDA) channels make it a factor in the treatment of depression. The present study investigated the level of serum magnesium in subjects diagnosed with depression in the city of Yazd in Iran. This cross-sectional study was done from January 2013 to January 2014 on 650 patients with depression who agreed to participate in this study. Diagnosis was made using the Beck Depression Inventory test (BDI-II); those scoring higher than 11 were sent to the medical school laboratory for further testing of serum magnesium levels. The mean age of the patients was 34.16 +/- 9.12 years. Of the 650 subjects, 195 were male (30 %) and 455 were female (70 %). The total mean serum magnesium was 2.1 +/- 0.26 mg/dl. The prevalence of hypomagnesemia 13.7 %, hypermagnesemia 8.3 %, and sub-optimal magnesium levels was 26.5 %. Sub-optimal prevalence in women (28.1 %) was higher than in men (26.2 %). A significant relationship was observed between depression and serum magnesium level (p = 0.02). The results indicated that the prevalence of hypomagnesemia in subjects diagnosed with depression is high compared to non-depressed individuals. Moreover, there was a significant relationship between hypomagnesemia and intensity of depression that suggests a role for this element in the pathogenesis of the disorder. The high sub-optimal prevalence among women indicates that increased attention should be paid to this group.

Biol Trace Elem Res. 2016 Jun; 171(2): 275-282.

The Role of Curcumin Administration in Patients with Major Depressive Disorder: Mini Meta-Analysis of Clinical Trials.

Major depression is a common, recurrent, and chronic disease that negatively affects the quality of life and increases the risk of mortality. Several studies have demonstrated that curcumin, the yellow-pigmented substance of the turmeric, possesses antidepressant properties. The aim of this review is to meta-analytically assess the antidepressant effect of curcumin in patients with major depressive disorders. We extensively searched the literature until August 2015. The random-effect model was used to calculate the pooled standardized difference of means (SMD). Subgroup analyses were also performed to examine the effect of different study characteristics on the overall model. Six clinical trials met the inclusion criteria. Overall, curcumin administration showed a significantly higher reduction in depression symptoms [SMD = -0.34; 95% confidence interval (CI) = -0.56, -0.13; p = 0.002]. Subgroup analyses showed that curcumin had the highest effect when given to middle-aged patients (SMD = -0.36; 95% CI = -0.59; -0.13; p = 0.002), for longer duration of administration (SMD = -0.40; 95% CI = -0.64, -0.16; p = 0.001), and at higher doses (SMD = -0.36; 95% CI = -0.59, -0.13; p = 0.002). The administration of new formulation of curcumin (BCM-95) had non-significantly higher effect on depression as compared with the conventional curcumin-piperine formula. We conclude that there is supporting evidence that curcumin administration reduces depressive symptoms in patients with major depression.

Phytother Res. 2016 Feb; 30(2): 175-183.

Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population.

Curcumin possesses many properties which may prevent or ameliorate pathological processes underlying age-related cognitive decline, dementia or mood disorders. These benefits in preclinical studies have not been established in humans. This randomized, double-blind, placebo-controlled trial examined the acute (1 and 3 h after a single dose), chronic (4 weeks) and acute-on-chronic (1 and 3 h after single dose following chronic treatment) effects of solid lipid curcumin formulation (400 mg as Longvida(R)) on cognitive function, mood and blood biomarkers in 60 healthy adults aged 60-85. One hour after administration curcumin significantly improved performance on sustained attention and working memory tasks, compared with placebo. Working memory and mood (general fatigue and change in state calmness, contentedness and fatigue induced by psychological stress) were significantly better following chronic treatment. A significant acute-on-chronic treatment effect on alertness and contentedness was also observed. Curcumin was associated with significantly reduced total and LDL cholesterol and had no effect on hematological safety measures. To our knowledge this is the first study to examine the effects of curcumin on cognition and mood in a healthy older population or to examine any acute behavioral effects in humans. Results highlight the need for further investigation of the potential psychological and cognitive benefits of curcumin in an older population.

J Psychopharmacol. 2015 May; 29(5): 642-651.

An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trial.

OBJECTIVE: To investigate the effectiveness of curcumin, a natural polyphenolic compound with antioxidant and anti-inflammatory activities, on the frequency of symptoms of anxiety and depression in obese individuals. METHODS: In this double blind, cross-over trial, 30 obese subjects were randomized to receive either curcumin (1 g/day) or placebo for a period of 30 days. Following a wash-out interval of 2 weeks, each subject was crossed over to the alternative regimen for a further 30 days. Severity of anxiety and depression was assessed at baseline and at weeks 4, 6 and 10 of the trial using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scales, respectively. RESULTS: Mean BAI score was found to be significantly reduced following curcumin therapy (P=0.03). However, curcumin supplementation did not exert any significant impact on BDI scores (P=0.7). CONCLUSION: Curcumin has a potential anti-anxiety effect in individuals with obesity.

Chin J Integr Med. 2015 May; 21(5): 332-338.

Pretreatment with curcumin attenuates anxiety while strengthens memory performance after one short stress experience in male rats.

It is observed that memories are more strengthened in a stressful condition. Studies have also demonstrated an association between stressful events and the onset of depression and anxiety. Considering the nootropic, anxiolytic and antidepressant-like properties of curcumin in various experimental approaches, we appraised the beneficial effects of this herb on acute immobilization stress-induced behavioral and neurochemical alterations. Rats in test group were administrated with curcumin (200mg/kg/day), dissolved in neutral oil, for 1 week. Both control and curcumin-treated rats were divided into unstressed and stressed groups. Rats in the stressed group were subjected to immobilization stress for 2h. After stress, the animals were subjected to behavioral tests. Immobilization stress induced an anxiogenic behavior in rats subjected to elevated plus maze test (EPM). Locomotor activity was also significantly increased following the acute immobilization stress. Pre-administration of curcumin prevented the stress-induced behavioral deficits. Highest memory performance was observed in stressed rats that were pre-treated with curcumin in Morris water maze (MWM). Brain malondialdehyde (MDA) levels, catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and acetylcholinesterase (AChE) activities were also estimated. Present study suggests a role of antioxidant enzymes in the attenuation of acute stress induced anxiety by curcumin. The findings therefore suggest that supplementation of curcumin may be beneficial in the treatment of acute stress induced anxiety and enhancement of memory function.

Brain Res Bull . 2015 Jun; 115: 1-8.

Depressive symptoms are associated with oxidative stress in middle-aged women: a cross-sectional study.

BACKGROUND: Oxidative stress is known to be a factor in various diseases. In this study, we investigated whether physical and psychological symptoms of menopause, cardiovascular parameters, body composition, and lifestyle factors are associated with oxidative stress in middle-aged women. METHODS: This cross-sectional study used baseline data collected in a previous study that examined the effects of a dietary supplement on a variety of health parameters in 95 women aged 40 to 60 years. Participants had been assessed for age, menopausal status, body composition, cardiovascular parameters, physical and psychological symptoms of menopause, and lifestyle factors. Urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG) level, an oxidative stress marker, had also been measured. Dichotomizing 8-OHdG levels as low (</=25 ng/mg creatinine) and high (>25 ng/mg creatinine), we sought to identify the health parameters that are associated with high 8-OHdG level. RESULTS: Women with a high 8-OHdG level had lower body weight, lower body mass index, lower body fat mass, higher body temperature, scored higher for both anxiety and depression on the Hospital Anxiety and Depression Scale (HADS), and consumed more alcohol. Multiple logistic regression analysis revealed that the HADS-depression subscale (HADS-D) score was the sole independent contributor to high 8-OHdG level (adjusted odds ratio, 1.23 per point increase in HADS-D score; 95 % confidence interval, 1.06-1.45). CONCLUSION: Depressive symptom score was shown to be independently associated with high 8-OHdG level in middle-aged women, suggesting a link between mood disorder and oxidative stress.

Biopsychosoc Med. 2016 10: 12.

Sertraline and curcumin prevent stress-induced morphological changes of dendrites and neurons in the medial prefrontal cortex of rats.

Stress induces structural and behavioral impairments. The changes in dendrites and neurons are accompanied by impairments in the tasks mediated by the medial prefrontal cortex (mPFC). The present study was conducted to evaluate the structural changes of the dendrites and neurons of the mPFC after stress using stereological methods. In addition, the effects of a natural and a synthetic substance, i.e., curcumin and sertraline, were evaluated. The rats were divided into 7 groups: stress + distilled water, stress + olive oil, curcumin (100 mg/kg/day), sertraline (10 mg/kg/day), stress + curcumin, stress + sertraline, and control groups. The animals were submitted to chronic variable stress for 56 days. The results showed an average 15% reduction in the length of the dendrites per neuron in the mPFC after stress (p < 0.004). The total spine density was reduced by 50% in the stress (+ olive oil or + distilled water) groups in comparison with the control group (p < 0.01). The main reduction was seen in the thin and mushroom spines, while the stubby spines remained unchanged. Mean volume and surface area of the neurons were decreased by 14% and 10% on average in the stress (+ distilled water or + olive oil) rats in comparison to the control rats, respectively (p < 0.01). The data revealed that treatment of stressed rats with curcumin or sertraline can prevent the loss of spines and reduction of dendrite length, volume and surface area of the neurons. Sertraline and curcumin can prevent structural changes of the neurons and dendrites induced by stress in the mPFC of rats.

Folia Neuropathol. 2015 53(1): 69-79.

Chronic Supplementation of Curcumin Enhances the Efficacy of Antidepressants in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.

Major depressive disorder is a devastating mental illness leading to a lifetime prevalence of higher than 16% on individuals. The treatment delay and inevitable adverse effects are major limitations of current depression interventions. Emerging evidence indicates that curcumin produced significant antidepressant properties in depression in both rodents and humans without adverse effects. Therefore, it is necessary to further clarify the antidepressant actions of curcumin and the underlying mechanism in depressed patients. A total of 108 male adults aged between 31 and 59 years were systematically recruited in Tianjin Anding Hospital. Subjects were administered the Chinese version of 17-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale that measures different scores of depressive symptoms. The subjects were asked to take 2 capsules containing either 1000 mg of curcumin or placebo soybean powder daily for 6 weeks on the basis of their current antidepressant medications. The plasma levels of interleukin 1beta, tumor necrosis factor alpha, brain-derived neurotrophic factor, and salivary cortisol were measured by enzyme-linked immunosorbent assay before and after curcumin or placebo treatment during the 6-week procedure. Chronic supplementation with curcumin produced significant antidepressant behavioral response in depressed patients by reduction of 17-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale scores. Furthermore, curcumin decreases inflammatory cytokines interleukin 1beta and tumor necrosis factor alpha level, increases plasma brain-derived neurotrophic factor levels, and decreases salivary cortisol concentrations compared with placebo group. These findings indicate the potential benefits of further implications of supplementary administration of curcumin to reverse the development of depression and enhance the outcome of antidepressants treatment in major depressive disorder.

J Clin Psychopharmacol. 2015 Aug; 35(4): 406-410.

Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 mug/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity.

Neuroscience. 2016 Apr 5; 319: 79-91.

Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke.

Carnosine is a naturally occurring pleotropic dipeptide which influences multiple deleterious mechanisms that are activated during stroke. Numerous published studies have reported that carnosine has robust efficacy in ischemic stroke models. To further evaluate these data, we have conducted a systematic review and meta-analysis of published studies. We included publications describing in vivo models of ischemic stroke where the neuroprotective efficacy of carnosine was being evaluated through the reporting of infarct volume and/or neurological score as outcomes. Overall efficacy was evaluated using weighted mean difference random effects meta-analysis. We also evaluated for study quality and publication bias. We identified eight publications that met our inclusion criteria describing a total of 29 comparisons and 454 animals. Overall methodological quality of studies was moderate (median = 4/9). Carnosine reduced infarct volume by 29.4% (95% confidence interval (CI), 24.0% to 34.9%; 29 comparisons). A clear dose-response effect was observed, and efficacy was reduced when carnosine was administered more than 6 h after ischemia. Our findings suggest that carnosine administered before or after the onset of ischemia exhibits robust efficacy in experimental ischemic stroke. However, the methodological quality of some of the studies was low and testing occurred only in healthy young male animals.

J Cereb Blood Flow Metab. 2016 Jul 8.

Effects of carnosine supplementation on glucose metabolism: Pilot clinical trial.

OBJECTIVE: Carnosine is a naturally present dipeptide in humans and an over-the counter food additive. Evidence from animal studies supports the role for carnosine in the prevention and treatment of diabetes and cardiovascular disease, yet there is limited human data. This study investigated whether carnosine supplementation in individuals with overweight or obesity improves diabetes and cardiovascular risk factors. METHODS: In a double-blind randomized pilot trial in nondiabetic individuals with overweight and obesity (age 43 +/- 8 years; body mass index 31 +/- 4 kg/m(2) ), 15 individuals were randomly assigned to 2 g carnosine daily and 15 individuals to placebo for 12 weeks. Insulin sensitivity and secretion, glucose tolerance (oral glucose tolerance test), blood pressure, plasma lipid profile, skeletal muscle ((1) H-MRS), and urinary carnosine levels were measured. RESULTS: Carnosine concentrations increased in urine after supplementation (P < 0.05). An increase in fasting insulin and insulin resistance was hampered in individuals receiving carnosine compared to placebo, and this remained significant after adjustment for age, sex, and change in body weight (P = 0.02, P = 0.04, respectively). Two-hour glucose and insulin were both lower after carnosine supplementation compared to placebo in individuals with impaired glucose tolerance (P < 0.05). CONCLUSIONS: These pilot intervention data suggest that carnosine supplementation may be an effective strategy for prevention of type 2 diabetes.

Obesity (Silver Spring). 2016 May; 24(5): 1027-1034.

Carnosine and the processes of ageing.

The causes of ageing are usually regarded as multifactorial; thus effective regulation might be achieved by intervention at multiple sites. It has been suggested that the endogenous dipeptide carnosine, also available as a food supplement, possesses anti-ageing activity and may achieve its reported age-alleviating effects via a number of mechanisms. Carnosine’s possible anti-ageing mechanisms are therefore discussed; the evidence suggests that inhibition of the mechanistic target of rapamycin and carbonyl scavenging may be involved.

Maturitas. 2016 Jun 22.

A Dietary Supplement Containing Cinnamon, Chromium and Carnosine Decreases Fasting Plasma Glucose and Increases Lean Mass in Overweight or Obese Pre-Diabetic Subjects: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Preventing or slowing the progression of prediabetes to diabetes is a major therapeutic issue. OBJECTIVES: Our aim was to evaluate the effects of 4-month treatment with a dietary supplement containing cinnamon, chromium and carnosine in moderately obese or overweight pre-diabetic subjects, the primary outcome being change in fasting plasma glucose (FPG) level. Other parameters of plasma glucose homeostasis, lipid profile, adiposity and inflammatory markers were also assessed. METHODS: In a randomized, double-blind, placebo-controlled study, 62 subjects with a FPG level ranging from 5.55 to 7 mmol/L and a body mass index >/= 25 kg/m(2), unwilling to change their dietary and physical activity habits, were allocated to receive a 4-month treatment with either 1.2 g/day of the dietary supplement or placebo. Patients were followed up until 6 months post-randomization. RESULTS: Four-month treatment with the dietary supplement decreased FPG compared to placebo (-0.24 +/- 0.50 vs +0.12 +/- 0.59 mmol/L, respectively, p = 0.02), without detectable significant changes in HbA1c. Insulin sensitivity markers, plasma insulin, plasma lipids and inflammatory markers did not differ between the treatment groups. Although there were no significant differences in changes in body weight and energy or macronutrient intakes between the two groups, fat-free mass (%) increased with the dietary supplement compared to placebo (p = 0.02). Subjects with a higher FPG level and a milder inflammatory state at baseline benefited most from the dietary supplement. CONCLUSIONS: Four-month treatment with a dietary supplement containing cinnamon, chromium and carnosine decreased FPG and increased fat-free mass in overweight or obese pre-diabetic subjects. These beneficial effects might open up new avenues in the prevention of diabetes.

PLoS One. 2015