Scientific evidence indicates that higher levels of blood glucose in the brain, due to the inability of the brain to process the glucose (impaired fasting glucose metabolism) is strongly linked to cognitive decline including brain shrinkage and dementia including Alzheimer's Disease (AD). Neurons in the brain must have a continuous supply of glucose, which is utilized as their primary energy source. Transport of glucose into the neuron is through the glucose transport proteins GLUT1 and GLUT3 which are not dependent on insulin. Since the brain is so dependent on GLUT1 and GLUT3 to sustain energy for the function of the neurons, any loss of GLUT functioning results in the death of neurons. Furthermore. the higher levels of uncontrolled glucose causes destructive pathological changes to the brain associated with Alzheimer's Disease. The impaired ability of the brain to properly metabolize glucose is often referred to as "type 3 diabetes". (1-6)
HYPERGLYCEMIA (Including High-Normal Glucose Levels). Dysregulation of glucose homeostasis leads to higher levels of glucose in brain tissue including brain shrinkage, and the formation of brain pathologies such as beta amyloid plaques and fibrils. Higher blood sugar levels (including high normal, prediabetes and type 2 diabetes) begin with insulin resistance, whereby blood glucose cannot be adequately absorbed by the cells, and glucose levels in the blood stream increase.
Higher plasma glucose levels is correlated to increases in brain glucose. Furthermore, this continues to be exacerbated when GLUT1 and GLUT3 transporters are decreased in function and/or number, and glucose is unable to reach the neurons. GLUT transporters are affected by glycation in diabetics, and may render the transport mechanism non-functional. Higher glucose levels correlate to the most severe loss of brain function in Alzheimer's Disease. (11)
Classifications of fasting blood glucose levels:
AMYLOID PLAQUES AND TAU FIBRIL ENTANGLEMENTS
Impaired glucose metabolism in brain tissue, including reduced levels of GLUT1 and GLUT3, are significantly linked to amyloid plaque accumulation and brain tau fibril entanglements.
Pathological changes in the brain linked to high blood glucose:
GLUCOSE TRANSPORTERS - Impact on Brain Glucose Metabolism
Natural Support for Glucose Homeostasis
NEUROTREX (Jujube, Wolfberry, Piperine, more)
HYPER LONGEVITY (Fucoidan, Piperine, more)
YELLOW LONGEVITY (Yellow Glucose Homeostasis)
MEMORY ACTION (Andrographolide, more)
(1) An Y, et al, Evidence for brain glucose dysregulation in Alzheimer's disease. Alzheimers Dement. 2017 Oct 19
(2) Cherbuin N, et al. Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology. 2012 Sep
(3) Mortby ME, et al, High "normal" blood glucose is associated with decreased brain volume and cognitive performance in the 60s: the PATH through life study. PLoS One. 2013 Sep
(4) Porter-Turner MM, et al. Relationship between erythrocyte GLUT1 function and membrane glycation in type 2 diabetes. Br J Biomed Sci. 2011
(5) Barros LF, et al. Near-critical GLUT1 and Neurodegeneration. J Neurosci Res. 2017 Nov
(6) Vogelsang P, et al. Reduced glucose transporter-1 in brain derived circulating endothelial cells in mild Alzheimer's disease patients. Brain Res. 2017 Nov 1
(7) Guo C, et al. Chronic hyperglycemia induced via the heterozygous knockout of Pdx1 worsens neuropathological lesion in an Alzheimer mouse model. Sci Rep. 2016 Jul
(8) Ying Liu, et al. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer disease. J Neurochem 2009 Oct.
(9) Liu F, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009.
(10) Gong CX, et al. O-GlcNAcylation: A regulator of tau pathology and neurodegeneration. Alzheimers Dement. 2016 Oct;
(11) Mittal K, et al. Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review. Diabetes Metab Syndr. 2016 Apr-Jun
(12) Zhang, C, et a. Antihyperglycaemic and organic protective effects on pancreas, liver and kidney by polysaccharides from Hericium erinaceus SG-02 in streptozotocin-induced diabetic mice. Scientific Reports 7, Article number: 10847 (2017)
(13) Cai H, et al. Lycium barbarum L. Polysaccharide (LBP) Reduces Glucose Uptake via Down-Regulation of SGLT-1 in Caco2 Cell. Molecules. 2017 Feb.
(14) Naik RR, et al. Andrographolide reorganise hyperglycaemia and distorted antioxidant profile in streptozotocin-induced diabetic rats. Cardiovasc Hematol Agents Med Chem. 2017 Oct
(15) Zhao Y, et al. Preventive effects of jujube polysaccharides on fructose-induced insulin resistance and dyslipidemia in mice. Food Funct. 2014 Aug
(16) Fang P, et al. Baicalin against obesity and insulin resistance through activation of AKT/AS160/GLUT4 pathway. Mol Cell Endocrinol. 2017 Jun
(17) Wan CP, et al. [Piperine regulates glucose metabolism disorder in HepG2 cells of insulin resistance models via targeting upstream target of AMPK signaling pathway]. Zhongguo Zhong Yao Za Zhi, 2017 Feb
(18) O'Neill HM. AMPK and Exercise: Glucose Uptake and Insulin Sensitivity. Diabetes Metab J. 2013 Feb
(19) Kim KJ, et al, Fucoidan regulate blood glucose homeostasis in C57BL/KSJ m+/+db and C57BL/KSJ db/db mice. Fitoweapia. 2012 Sep
(20) Yu W, wt al. Fucoidan ameliorates pancreatic β-cell death and impaired insulin synthesis in streptozotocin-treated β cells and mice via a Sirt-1-dependent manner. Mol Butr Food Res. 2017 Oct;
(21) de Las Heras N, et al. Molecular factors involved in the hypolipidemic- and insulin-sensitizing effects of a ginger (Zingiber officinale Roscoe) extract in rats fed a high-fat diet. Appl Physiol Nutr Metab. 2017 Feb
(22) Bumke-Vogt C, et al. The flavones apigenin and luteolin induce FOXO1 translocation but inhibit gluconeogenic and lipogenic gene expression in human cells. PLoS One. 2014 Aug
(23) Zhao NJ, et al. Curcumin suppresses Notch‑1 signaling: Improvements in fatty liver and insulin resistance in rats. Mol Med Rep. 2018 Jan;
Protective macular pigments consist of lutein, zeaxanthin and meso zeaxanthin which act as powerful lipid antioxidants as well as functioning as an anti-inflammatory in the retina. In both the retina and the brain, these pigments are readily absorbed into the cellular membranes and orient themselves perpendicular in the membrane which acts to stabilize the cellular membrane.(1) The cellular membrane is made from unsaturated fats, which are very susceptible to free radical induced oxidative damage by high energy short wave light (such as blue light). As a potent lipid antioxidants, lutein, zeaxanthin and meso zeaxanthin signifcantly boost protection of the cellular membrane, and thereby protecting cells of the retina cells and neurons in the brain.(2)
VISION VITALITY MAX (Lutein | Zeaxanthin | Mesozeaxanthin)
(1) Subczynski WK, et al. Location of macular xanthophylls in the most vulnerable regions of photoreceptor outer-segment membranes. Arch Biochem Biophys. 2010 Dec
(2) Widomska J, et al. Can Xanthophyll-Membrane Interactions Explain Their Selective Presence in the Retina and Brain? Foods. 2016 Mar.
(3) Neelam K, et al. Putative protective role of lutein and zeaxanthin in diabetic retinopathy. Br J Opthalmol. 2017 May
(4) Gong X, et al. Role of macular xanthophylls in prevention of common neovascular retinopathies: retinopathy of prematurity and diabetic retinopathy. Arch Biochem Biophys. 2015 Apr.
(5) Orhan C, et al. Mesozeaxanthin Protects Retina from Oxidative Stress in a Rat Model. J Ocul Pharmacol Ther. 2016 Nov.
(6) Binxing Li, et al. Studies on the Singlet Oxygen Scavenging Mechanism of Human Macular Pigment.Arch Biochem Biophys, 2010 Dec.
(7) Firdous AP, et al. Amelioration of radiation-induced damages in mice by carotenoid meso-zeaxanthin. Int J Radiat Biol. 2013 Mar
Energy generation from brown adipose tissue (thermogenesis) is important for maintaining longevity, reducing obesity and supporting energy homeostasis. Brown adipose tissue (BAT) is central to physiological energy homeostasis. Enhancing brown adipose tissue reduces obesity, diabetes, insulin resistance and non-alcoholic fatty liver..
BAT dissipates energy in the form of heat through increased theromgenesis.(1) Browning of white adipose tissue, which converts characteristics of white adipose tissue to brown adipose tissue, increases expression of the thermogenic mitochondrial protein UCP-1. The uncoupling protein 1 (UCP-1) is a potent protein which shifts energy from ATP to heat.
Greater amounts of brown adipose tissue and the thermogenic capacity of the tissue are indicative of youth. With age, brown adipose tissue is decreased, while white adipose tissue becomes predominant and accelerates aging via inflammation and insulin resistance. .
GLUCORAPHANIN - Is a precursor of sulforaphane.
In laboratory mice fed a high fat diet, glucoraphanin supplementation promoted increased energy expenditures via an increase in UCP-1 protein expression in adipose deposit areas. Furthermore, results included decreases in weight, increased insulin sensitivity and improved glucose tolerance.(2)
PTEROSTILBENE - Studied in obese rats, pterostilbene increased the thermogenic capability of the BAT through an upregulation of Ucp1 protein expression..(3)
PURPLE LONGEVITY (Pterostilbene)
(1) Galmozzi A, et al. ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue. Cell Rep. 2014. Dec.
(2) Nagata N, et al. Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice. Diabetes. 2017 Feb 16.
(3) Aguirre L, et al. Effects of pterostilbene in brown adipose tissue from obese rats. J Physiol Biochem. 2017 Feb 27
In humans, there are two types of adipose tissue. White adipose tissue and brown adipose tissue. White adipose tissue is associated with excessive fat storage, obesity, insulin resistance and diabetes. Whereas, brown adipose tissue has the opposite effect - producing energy, reducing fat storage and obesity, while increasing insulin sensitivity and reducing diabetes. Further, increasing expression of brown adipose tissue (adipocytes) may also be correlated with increases in longevity.
Newborns have the greatest amount of brown fat, which helps provide a source of heat, but gradually decreases with age. Adults have a predominance of white adipose tissue which correlate with America's obesity epidemic.
BROWN ADIPOSE TISSUE
NUTRITION SUPPLEMENT SUPPORT:"Browning" of White Adipocytes.
Research indicates that fat storing white adipocytes may be altered to take on the characteristics of energy producing brown adipocytes. Such changes to white adipocytes may be an effective strategy for reducing obesity and obesity related disorders (such as insulin resistance and diabetes). Improving insulin sensitivity is a factor not only in diabetes, but also considered significant in longevity.
Improvement in number and function of mitochondria during brown fat adipogenesis. This may result in higher energy brown adipose tissue enabling even a stronger thermogenic response
XGEVITY Glucoraphanin (precursor of Sulforaphane)
CURCUMIN XTRA-MAX (includes Andrographolide)
BLUE NATURALLY (high anthocyanins and C3G)
(1) Inagaki T, et al. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol. 2016 Jun 2
(2) Qian SW, et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA. 2013 Feb
(3) Mookerjee SA, et al. Mitochondrial Uncoupling and Lifespan. Mech Ageing Dev. 2010 Jul - Aug.
(4) Zhang HQ, et al. Sulforaphane induces adipocyte browning and promotes glucose and lipid utilization. Mol Nutr Food Res. 2016 May 24
(5) Lone J, et al. Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J Nutr Biochem. 2016 Jan
(6) Ding L, et al. Andrographolide prevents high-fat diet-induced obesity in C57BL/6 mice by suppressing the sterol regulatory element-binding protein pathway. J Pharmacol Exp Ther. 2014 Nov
(7) You Y, et al. Mulberry and mulberry wine extract increase the number of mitochondria during brown adipogenesis. Food Funct. 2015 Feb
How and to what extent microbes influence on health is a relatively new area of study. Amazingly, the influence of gut microbiota on general health and longevity is only now becoming understood. Recent attention is scientific areas concern the importance of intestinal microbes and how they affect not only health of the the gut but also overall health of the body.(1) An area of keen interest is the production of Short Chain Fatty Acids (SCFAs) by microbial fermentation in the gut and how it can significantly improve health.(2)
Short Chain Fatty Acids (SCFAs - acetic acid, propionic acid and butyric acid) are produced as a fermentation byproduct of soluble fiber (e.g nuts, seeds, certain vegetables) by microbes in the large intestine.
Among the beneficial effects of SCFA's include:
THE ROLE OF TAURINE IN SHORT CHAIN FATTY ACID PRODUCTION.
Furthermore, research indicates that taurine supplementation may significantly improve the intestinal microbiotic environment by increasing the production of SCFAs and decreasing inflammatory concentrations of serum lipopolysaccharides (LPS). LPS induced inflammation is a common issue facilitated by the processed western diet.(5)
LONGEVITY NATURALLY (High Taurine Complex)
(1) Andoh A. Physiological Role of Gut Microbiota for Maintaining Human Health. Digestion. 2016 Feb 9
(2) KeenanMJ, et al. Improving healthspan via changes in gut microbiota and fermentation. Age (Dordr). 2015 Oct.
(3) Hartl FU. Cellular Homeostasis and Aging. Annu Rev Biochem. 2016 Apr 6.
(4) Puddu A, et al. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediators Inflamm. 2014
(5) Yu H, et al. Effects of taurine on gut microbiota and metabolism in mice. Amino Acids. 2016 Mar 30.
What is the most precise predictive measure of cardiovascular disease (and diabetes)? Common dogma continues to hold LDL ("bad" cholesterol) as the most accurate measure. However, recent studies research indicate a much stronger correlation between high triglyceride-to-HDL ratios in predicting both cardiovascular disease and the development of diabetes. In a study by the American Heart Association, individuals with the highest triglyceride-HDL ratios were 16x's more likely to suffer a cardiovascular event (i.e. heart attack) as compared to individuals with the lowest triglyceride-HDL ratios. The triglyceride-to-HDL ratio is significantly stronger in predicting cardiovascular events than "high cholesterol" numbers or LDL-to-HDL ratios.(1)
HIGH TRIGLYCERIDES - the dangerous effect of high levels of triglycerides on the cardiovascular system is multi-faceted. Negative effects of high triglyceride levels:
CITRUS BERGAMOT (Bergamonte®) POLYPHENOLS
Bergamote® (an extract from Bergamot citrus in Italy), is called by some advocates as the ideal natural cardiovascular support supplement. Bergamonte decreases the triglyceride-to-HDL ratio by both decreasing plasma triglycerides and increasing HDL.(3)
Bergamonte® is a registered trademark of HP Ingredients
VASCULAR STRENGTH (with Bergamonte®)
(1) Turak O, et al. The Role of Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio to Predict New Cardiovascular Events in Essential Hypertensive Patients.Journal of Clinical Hypertension. Jan 2016.
(2) Bertsch RA, et al. Study of the use of lipid panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk. Perm J. 2015 Fall.
(3) HP Ingredients Research. 2016
(4) Proshkina EN, et al. Basic mechanisms of longevity: A case study of Drosophila pro-longevity genes. Ageing Res. Rev. 2015 Nov;
(5) Daskaopoulos EP, et al. AMPK in cardiac fibrosis and repair. Actions beyond metabolic regulation. J Mol. Cell Cardiol. 2016 Jan.
(6) Parafati M, et al. Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome. J Nutr Biochem. 2015 Sept.
(7) Zang M, et al. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes. 2006 Aug.
Brain aging is one of the inevitable signs of aging. Cognitive decline and dementia takes many forms, among the most common is Alzheimer's Disease (AD). AD is estimated to comprise 60-70% of all dementia cases worldwide. Similarly, the report from the
World Health Organization (WHO) states that "dementia is one of the major causes of disability and dependency among older people worldwide." (1) At this time, the only medicines available to treat AD only treat the symptoms and have no effect on the progression of the disease. In the near future, it is estimated that cases of AD will grow at an alarming rate, given the aging of the world's population.
Aging is the primary risk factor for Alzheimer's Disease. Neuronal cell death and synaptic degradation in Alzheimer's is attributed to gradual build-up of toxic mis-folded proteins (beta amyloid) and aggregation of tau protein fibrils and chronic brain inflammation. Each of these defective proteins kill neurons and synapses, rendering a degeneration of brain physical and mental function.
Yellows and golds in nature support brain health, and may reduce some of the factors associated with Alzheimer's Disease based upon animal research models. Research is strongly supportive of the role yellows can play in defusing brain inflammation, protecting against beta amyloid toxicity, tau fibril aggregation, microvascular circulation and provide protection of vital neurons and synapses.
RESEARCH - FACTORS INVOLVED IN BRAIN HEALTH
(1) Glycogen synthase kinase 3 (GSK3) - a kinase enzyme which has been implicated in many diseases including Alzheimer's Disease, type 2 diabetes and cancer. In Alzheimer's Disease GSK3 has a key role in the accumulation of the toxic proteins. Inhibitors of GSK3 reduce beta amyloid and tau protein toxic buildup and are now a target of researchers.(2)
(2) Beta Amyloid and Neurofibrillary (Tau) Tangles - Consensus of the scientific community is that beta amyloid, a toxic protein in the brain, is the initiator for further cascading events in the Alzheimer's progression. Beta amyloid accumulation then triggers a second protein toxin tau protein tangles (tau hyperphosphorylation).(3) Both proteins act as neurotoxins in the neurons and synapses. It appears that the over accumulation of Beta Amyloid stems from increased production and the inability to remove the excess.(4) This could involve a defect in the cellular ability to remove defective proteins (proteolysis including autophagy) (5) and / or an impairment of cerebral fluid removal system from the brain of the toxic proteins.
(3) Chronic Microglial Inflammation Over stimulation of the microglia in the brain is a primary cause of neuro inflammation. Microglia in brain become overly activated as a result of beta amyloid accumulation - theryby creating an inflammatory state in the brain, which further accelerates the destruction of brain neurons and synapses. (6)
Paradoxically, microglia may also play a protective role by clearing amyloid plaque via phagocytosis. Nrf2 activation in the microglia may support increase in phagocytosis activity, which has been demonstrated using sulforphane in test animals in brain hematoma clearance.(7) Sulforaphane also provides direct protection to brain from amyloid.(8) Furthermore, studies indicate that taurine is able to reduce inflammation in the brain by switching the type of microglia from M1 (proinflammatory) to M2 (which promotes phagocytosis).(9) Taurine also acts directly on protein aggregates ameliorating toxicity.(10)
(4) Defective insulin Signaling (Type 2 diabetes). There is a strong association between type 2 diabetes and cognitive decline.(11, 12) Insulin resistance in the brain, associated with type 2 diabetes, is correlated with Alzheimer's Disease.(12) Insulin resistance increases tau protein hyperphosphorylation (forming toxic tau protein tangles). EGCG (from Green Tea) has been shown to attenuate insulin resistance in the hippocampus area of the brain, thereby improving memory deficits related to Alzheimer's Disease. As part of the effect, EGCG inhibited glycogen synthase kinase-3β (GSK3), which plays a role in insulin resistance. Diet induced insulin resistance also has been shown to increase the manufacture of beta amyloid in the brain.(13)
(5) Vascular Circulation (in brain) There is a strong correlation between neurovascular disorder and intensity of brain dysfunction in the progression of Alzheimer's Disease.(14) Decline in blood flow to the brain affects the neurons and their ability to function and survive. Areas of the brain which deficient blood flow show white areas in brain MRIs, referred to as "white matter lesions" and are common in the brains of Alzheimer's patients and are caused by affected blood flow to a region of the brain.(15) Patients with white matter lesions are associated with more rapid decreased cognition (16) and also contribute to occurrence of depression experienced in Alzheimer's patients.(17)
(6) Iron and Brain Aging. While iron is a necessary mineral for good health, excessive accumulation in the brain is highly oxidative and inflammatory. Removal of excess iron from the brain, and iron homeostasis, will support healthy brain function and reduce potential for neurodegenerative diseases such as Alzheimers. Iron chelators, which remove excess cellular iron are effective in promoting brain health.(18)
KEY INGREDIENTS FOR SUPPORT OF BRAIN HEALTH
LONGEVITY NATURALLY (Yellows plus Taurine)
XGEVITY (Yellows plus Sulforaphane)
(1) World Health Organization (WHO). Dementia. March 2015.
(2) Maqbool M, et al. Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease. Eur J Med Chem. 2015 Oct 21
(3) Musiek ES, et al. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci. 2015 Jun
(4) Gallina P, et al. Aβ Clearance, “hub” of Multiple Deficiencies Leading to Alzheimer Disease. Front Aging Neurosci. 2015;
(5) Salminen A, et al. Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome. Prog Neurobiol. 2013 Jul-Aug.
(6) Wang WY, et al. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 2015 Jun
(7) Zhao X, et al. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. J Neurochem 2015 Apr
(8) Zhang R, et al. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions. Am J Alzheimers Dis Other Demen. 2015 Mar.
(9) Ward RJ, et al. Ageing, neuroinflammation and neurodegeneration. Front Biosci (Schol Ed) 2015 Jun
(10) Chaturvedi SK, et al. Biophysical insight into the anti-amyloidogenic behavior of taurine. Int J Biol Macromol. 2015 Sep
(11) Li M, et al. Fasting and systemic insulin signaling regulate phosphorylation of brain proteins that modulate cell morphology and link to neurological disorders. J Biol Chem. 2015 Oct 23
(12) Sato N, et al. The roles of lipid and glucose metabolism in modulation of β-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Front Aging Neurosci 2015 Oct
(13) Ho L, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004 May
(14) Pachalska M, et al. Vascular Factors and Cognitive Dysfunction in Alzheimer Disease. Med Sci Monit. 2015 Nov
(15) Alzheimer's Society. 2015.
(16) Hanaoka T, et al. Relationship between white matter lesions and regional cerebral blood flow changes during longitudinal follow up in Alzheimer's disease. Geriatr Ferontol Int 2015 Aug 5.
(17) Lee JJ, et al. Impact of White Matter Lesions on Depression in the Patients with Alzheimer's Disease. Psychiatry Investig 2015 Oct
(18) Ward RJ, et al. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014 Oct
ALZHEIMERS INGREDIENTS RESEARCH:
(19) Tapia-Rojas C, et al. Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3β: autoregulation of GSK-3β in vivo. Biochem J. 2015 Mar 1
(20) Wang C, et al. Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. Eur J Pharmacol. 2014 Oct
(21) Venigalla M, et al. Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease. Neurochem Int. 2015 Oct 31
(22) Venigalla M, et al. Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease. Neural Regen Res. 2015 Aug;
(23) Jia N, et al. (-)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus. Mol Cell Biochem. 2013 Aug
(24) de Oliverira. The Dietary Components Carnosic Acid and Carnosol as Neuroprotective Agents: a Mechanistic View. Mol Neurobiol. 2015 Nov 9
(25) Rasoolijazi H, et al. The protective role of carnosic acid against beta-amyloid toxicity in rats. Scientific WorldJournal 2013 Oct 24
(26) Azad N, et al. Neuroprotective effects of carnosic Acid in an experimental model of Alzheimer's disease in rats. Cell J. 2011 Spring.
(27) Shi X, et al. Curcumin inhibits Aβ-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways. Neurosci Lett. 2015 May
(28) Rezai-Zadeh K, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflammation. 2008 Sep 25
(29) Park SY, et al. α-Iso-cubebene exerts neuroprotective effects in amyloid beta stimulated microglia activation. Neurosci Lett. 2013 Oct 25
(30) Bustanji Y, et al. Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation. J Enzyme Inhib Med Chem. 2009 Jun.
(31) Mathew M, et al. In vitro evaluation of anti-Alzheimer effects of dry ginger (Zingiber officinale Roscoe) extract.
(32) Dong HJ, et al. Curcumin attenuates ischemia-like injury induced IL-1β elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-κB activation. Neuro Sci. 2014 Sep
(33) Mann GE. Nrf2-mediated redox signalling in vascular health and disease. Free Radic Biol Med. 2014 Oct.
(34) Baum L, et al. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis. 2004 Aug
(35) Oboh G, et al. Antioxidant and inhibitory effect of red ginger (Zingiber officinale var. Rubra) and white ginger (Zingiber officinale Roscoe) on Fe(2+) induced lipid peroxidation in rat brain in vitro. Exp Toxicol Pathol. 2012 Jan
(36) Hofer T, et al. Comparison of food antioxidants and iron chelators in two cellular free radical assays: strong protection by luteolin. J Agric Food Chem. 2014 Aug 20
(37) Mladěnka P, et al. In vitro analysis of iron chelating activity of flavonoids. J Inorg Biochem. 2011 May
(38) Mandel SA, et al. Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J Alzheimers Dis. 2008 Oct
(39) Lavich IC, et al. Sulforaphane rescues memory dysfunction and synaptic and mitochondrial alterations induced by brain iron accumulation. Neuroscience. 2015 Aug 20.