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	Low-dose lithium uptake promotes longevity in humans By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	NATURAL ANTI-AGING MEDICINES
	Eur J Nutr. 2011 Aug; 50(5): 387–389. Published online 2011 Feb 8. doi: 10.1007/s00394-011-0171-x PMCID: PMC3151375 PMID: 21301855 Low-dose lithium uptake promotes longevity in humans and metazoans Kim Zarse,1 Takeshi Terao,2 Jing Tian,1 Noboru Iwata,3 Nobuyoshi Ishii,2 and Michael Ristow1,4 Author information Article notes Copyright and License information Disclaimer This article has been cited by other articles in PMC. Go to: Abstract Purpose Lithium is a nutritionally essential trace element predominantly contained in vegetables, plant-derived foods, and drinking water. Environmental lithium exposure and concurrent nutritional intake vary considerably in different regions. We here have analyzed the possibility that low-dose lithium exposure may affect mortality in both metazoans and mammals. Methods Based on a large Japanese observational cohort, we have used weighted regression analysis to identify putative effects of tap water-derived lithium uptake on overall mortality. Independently, we have exposed Caenorhabditis elegans, a small roundworm commonly used for anti-aging studies, to comparable concentrations of lithium, and have quantified mortality during this intervention. Results In humans, we find here an inverse correlation between drinking water lithium concentrations and all-cause mortality in 18 neighboring Japanese municipalities with a total of 1,206,174 individuals (β = −0.661, p = 0.003). Consistently, we find that exposure to a comparably low concentration of lithium chloride extends life span of C. elegans (p = 0.047). Conclusions Taken together, these findings indicate that long-term low-dose exposure to lithium may exert anti-aging capabilities and unambiguously decreases mortality in evolutionary distinct species. Keywords: Trace elements, Lithium, Mortality, Longevity, Human, C. elegans Go to: Introduction Lithium (Li+) is a nutritionally essential trace element found predominantly in plant-derived foods and drinking water [1, 2]. Environmental Li+ exposure and concurrent intake vary considerably from region to region [2, 3]. The trace element Li+ is typically present in all human organs and tissues, and is equally distributed in body water, while Li+ is absorbed from the intestinal tract and excreted by the kidneys [2]. Whereas deficiency of Li+ causes behavioral abnormalities and reduced litter size in rats, defined human Li+ deficiency diseases are unknown [2]. While the physiological functions of Li+ are mostly unresolved, high-dose lithium chloride (LiCl) is widely used to treat psychiatric conditions like bipolar disorder since 1949 [4–6]. Additionally, nutritional Li+ uptake may affect mental health in humans at sub-pharmacological, i.e. low micromolar doses. In particular, environmental Li+ exposure may be associated with reduced suicide rates [2, 7, 8]. We now have analyzed whether environmental low-dose Li+ exposure may affect mortality in a large Japanese cohort, and have additionally tested whether comparably low concentrations of Li+ may affect life span of a model organism for anti-aging studies, the roundworm Caenorhabditis elegans. Go to: Subjects, materials and methods Observational cohort All methods and materials related to the human sample have been previously described [8]. This study is based on the population of Oita prefecture in the year 2006, at that time totaling 1,206,174 individuals that are distributed over 18 municipalities with differing individual population sizes. Standardized mortality ratios Taking the difference in gender and age distribution of individual municipality populations into account, the standardized mortality ratio (SMR) was calculated for each individual municipality. SMR is an indirect method of adjusting a mortality rate, defined as the number of observed deaths in an individual municipality population divided by the number of expected deaths, compared with the gender- and age-matched general population [8]. Tap water lithium levels Lithium levels in the tap water suppliers of each municipality were measured using ion chromatography at Oita City Waterworks Bureau or by using mass spectroscopy at Oita Yakuzaishi Kensa Center [8]. Both methods have a sensitivity of 0.1 mg/L. Lithium levels of drinking water were measured at multiple water suppliers in the same municipality, and the median value was calculated for each municipality. Although lithium levels were typically measured only once per supplier, we observed a very small time-dependent fluctuation in concentrations: the correlation coefficient between the lithium levels and those re-quantified after one year in the same places was 0.998. The distribution of median lithium levels was considerably skewed (skewness = 3.39; kurtosis = 12.80). We thus had to employ logarithmic transformation (thereafter: skewness = 0.002; kurtosis = 0.075) before applying parametric statistical procedures. Because of considerable differences in population size across the 18 municipalities, weighted least squares regression analysis, adjusted for the size of each population, was used to investigate the association of lithium levels in drinking water and the SMRs [8]. C. elegans life span analysis The C. elegans strain used was Bristol N2. All experiments were performed exactly as previously described [9] except that streptomycin and 5-fluoro-2′-deoxyuridine were omitted, and synchronization was performed using an overnight egg-laying period (i.e. without applying bleach to eggs), as previously described elsewhere [10]. Living E.coli OP50 bacteria were used as the only food source. Analytical grade lithium chloride was purchased from Sigma–Aldrich (Munich, Germany). Go to: Results Analyzing overall mortality data from 1,206,174 individuals in Oita prefecture of Japan regarding their possible correlation with drinking water Li+ concentrations, we find that tap water Li+ levels in the 18 municipalities within the Oita prefecture are inversely associated with overall mortality rates adjusted for gender and age (β = −0.661, p = 0.003) (Fig. 1a). We additionally adjusted for suicide rates in this prefecture, since these have been previously shown to be negatively associated with tap water Li+ levels in this particular cohort [8]. After additional adjustment for suicide, overall mortality was still inversely associated with tap water Li+ levels (β = −0.580, p = 0.037) (data not depicted). This inverse correlation suggests that Li+ exposure may contribute to reduced overall mortality in humans independent of suicide risk. Fig. 1 Low-dose lithium exposure modulates mortality. a depicts data from 18 different Japanese municipalities which are named and color coded on the right-hand side. The numbers of inhabitants are reflected by the respective diameter of circles. The X-axis shows logarithmic median tap water lithium concentration, the Y-axis depicts the standardized mortality ratio, defined as number of observed deaths divided by the number of expected deaths. b depicts are mean values (±SEM) of three separate experiments with approximately one hundred of C. elegans roundworms per experiment and condition. Black circles reflect control animals, open circles reflect animals that were continuously exposed to 10 μM lithium chloride LiCl has been previously shown to extend life span of a model organism for anti-aging studies, the roundworm Caenorhabditis elegans, when applied at high, i.e. non-nutritional doses of 5 mM and above [11]. However, drinking water Li+ concentrations in the Oita prefecture ranged from 0.7 to 59 μg/L only [8], the latter equaling a concentration of 8.5 μM. Hence, we have continuously exposed several hundreds of C. elegans in separate experiments to 1 and 10 μM LiCl, respectively. We found mortality in populations exposed to 10 μM of LiCl to be decreased (p = 0.047) (Fig. 1b), while a concentration of 1 μM of LiCl had no detectable effect on C. elegans life span (data not shown). Go to: Discussion Our findings indicate that low-dose Li+ exposure causes reduced mortality in C. elegans, and that these life span-extending capabilities of low-dose Li+ can be observationally translated into reduced overall mortality in humans that have been exposed to comparable amounts of Li+ in a similar long-term fashion. It should be noted, however, that the findings in humans are observational and hence cannot provide a causal link between high-level Li+ intake on the one hand, and reduced mortality on the other hand. On a theoretical basis, a life-long intervention study in humans would be required to provide causal evidence for mortality-reducing effects of low-dose lithium supplementation. Such a study, for obvious reasons, cannot be materialized. Hence, we used a typical model organism for anti-aging studies, C. elegans, to test whether low-dose Li+ levels similar to those observed in some areas of the Oita prefecture, i.e. 10 μM, may actually cause reduced mortality. Based on previously published evidence from the Lithgow laboratory, a 1000-fold higher concentration extends C. elegans life span by 36% also by reducing expression of the C. elegans ortholog of a histone demethylase named LSD-1 in mammals and T08D10.2 in C. elegans, respectively. It hence is of little surprise that the concentration employed in the current study exerts less pronounced effects on life span of C. elegans. However and most importantly, this low concentration causes reduced mortality, suggesting that the effects of a similar exposure of humans within the Oita prefecture in regard to reduced mortality are not a mere coincidence, but rather reflect unresolved molecular effects on human mortality that clearly require further investigation. Lastly and given the long-standing psychiatric experience with high-dose Li+ supplementation in humans, these findings raise the possibility that readily available low-dose Li+ supplementation at non-toxic doses may not only promote mental health and impair suicide risk [2, 7, 8] but also may reduce overall mortality in humans. Go to: Acknowledgments This work is part of the research program of the Jena Centre for Systems Biology of Ageing—JenAge funded by the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung—BMBF; support code: 0315581). Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Go to: References 1. Anke M, Arnhold W, Groppel U, Krause U. The biological importance of lithium. In: Schrauzer GN, Klippel KF, editors. Lithium in biology and medicine. Weinheim: VCH Verlag; 1991. pp. 149–167. [Google Scholar] 2. Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 2002;21:14–21. [PubMed] [Google Scholar] 3. Zaldivar R. High lithium concentrations in drinking water and plasma of exposed subjects. Arch Toxicol. 1980;46:319–320. doi: 10.1007/BF00310450. [PubMed] [CrossRef] [Google Scholar] 4. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349–352. [PubMed] [Google Scholar] 5. Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162:1805–1819. doi: 10.1176/appi.ajp.162.10.1805. [PubMed] [CrossRef] [Google Scholar] 6. Rapoport SI, Basselin M, Kim HW, Rao JS. Bipolar disorder and mechanisms of action of mood stabilizers. Brain Res Rev. 2009;61:185–209. doi: 10.1016/j.brainresrev.2009.06.003. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 7. Schrauzer GN, Shrestha KP. Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res. 1990;25:105–113. doi: 10.1007/BF02990271. [PubMed] [CrossRef] [Google Scholar] 8. Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N. Lithium levels in drinking water and risk of suicide. Br J Psychiatry. 2009;194:464–465. doi: 10.1192/bjp.bp.108.055798. [PubMed] [CrossRef] [Google Scholar] 9. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007;6:280–293. doi: 10.1016/j.cmet.2007.08.011. [PubMed] [CrossRef] [Google Scholar] 10. Lithgow GJ, White TM, Melov S, Johnson TE. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A. 1995;92:7540–7544. doi: 10.1073/pnas.92.16.7540. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 11. McColl G, Killilea DW, Hubbard AE, Vantipalli MC, Melov S, Lithgow GJ. Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J Biol Chem. 2008;283:350–357. doi: 10.1074/jbc.M705028200. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 2 weeks ago By Gnome...
	Vitamin D, Oxidative Stress, Immunity, and Aging By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	NATURAL ANTI-AGING MEDICINES
	Great Reads, Cheers! 2 weeks ago By Gnome...
	Olives and Olive Oil in Health and Disease Prevention By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	NATURAL ANTI-AGING MEDICINES
	Utilized in spiritual events related to health, the nutritional and health-promoting benefits of olives and olive oils have been confirmed by an ever-increasing body of scientific research. From cardiovascular benefits to anti-microbial, anti-cancer, antioxidant activity and also impacts on macrophages and apoptosis to mobile and pathophysiological processes, olives and olive oils are showing vital in lots of healthful methods. For instance, reactive parts in olive oils or olive oil spin-offs have currently been separated and also determined. These include tyrosol, hydroxytyrosol, 3,4-dihydroxyphenyl acetic acid elenolic acid, and oleuropein. Oleic acid is the main monosaturated fatty acid of olive oil. These have putative protective results and also modulate the biochemistry of various cell types, consisting of those of the vascular system. Some yet not all parts have been defined by their presumptive medicinal residential or commercial properties. The usage of these abovementioned products might have helpful applications in other diseases. However, for this cross-fertilization to occur, a detailed understanding of olives as well as olive oils are called for. Locating this expertise in a single volume supplies a key resource for scientists in various food and dietary functions. Key Functions: * Checks out olives and also olive oil from their general facets to the in-depth degree of important micro-and micronutrients * Consists of coverage of different techniques for analysis to assist researchers and also chemists identify one of the ideal alternatives for their very own research studies, including those of olive-related compounds in various other foods * Relates, in a single volume source, info for food and also dietary chemists, pharmaceutical scientists, nutritional experts, and also diet professionals * Presents info in 3 crucial categories: General facets of olives and olive oils; Nutritional, medicinal and metabolic properties of olives as well as olive oil; Details elements of olive oil and also their impacts on tissue and also body systems. Great READS! Cheers! ALSO interesting: 2 weeks ago By Gnome...
	Glutathione and Sulfur Amino Acids in Human Health and Disease By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	NATURAL ANTI-AGING MEDICINES
	The duties of glutathione and sulfur amino acids in human health and wellness glutathione (?-L-glutamyl-L-cysteinyl glycine, GSH) is a major antioxidant functioning as a complimentary radical scavenger that protects the cell from reactive oxygen varieties (ROS). Sulfur amino acids (SAAs), such as methionine and cysteine, play a vital role in maintaining health. GSH exhaustion, along with changes of SAA metabolic rate, is connected to a host of illness states, including liver cirrhosis, different pulmonary diseases, myocardial anemia and also reperfusion injury, aging, Parkinson's illness, Alzheimer's illness, sepsis, and others. This book offers researchers a thorough evaluation of the biochemistry, absorption, metabolic rate, biological activities, illness avoidance, and also health promotion of glutathione and also sulfur amino acids. The twenty-two chapters check out such topics as Chemistry, absorption, transport, as well as metabolic process of GSH and also sulfur amino acids anti-oxidants as well as cleansing properties of GSH and sulfur amino acids, highlighting the enzymatic systems involved in antioxidant defense biological activities of GSH and sulfur amino acids as well as their duty in modulating cell processes role of GSH and also sulfur amino acid deficiency and also modification in the onset of illness and also in aging protective results exerted by GSH and sulfur amino acids when utilized as medications, practical foods, and nutraceuticals in humans as well as animals special focus is paid to the molecular devices for the modulation of transcription factors and also enzyme activities, along with the dietary and therapeutic significance of dietary sulfur amino acids as received human and also animal versions. With greater than 2,000 scientific referrals, this publication offers food scientists, nutritional experts, biochemists, food engineers, chemists, molecular biologists, as well as public health specialists a comprehensive as well as up-to-date exam of glutathione and also sulfur amino acids in human wellness as well as condition.Glutathione (γ-L-glutamyl-L-cysteinyl glycine, GSH) is a vital antioxidant working as a totally free radical scavenger that shields the cell from reactive oxygen varieties (ROS). Sulfur amino acids (SAAs), such as methionine and cysteine, play a crucial duty in the upkeep of wellness. GSH exhaustion, in addition to alterations of SAA metabolic rate, is linked to a host of condition states consisting of liver cirrhosis, various lung diseases, myocardial ischemia and reperfusion injury, aging, Parkinson's condition, Alzheimer's disease, blood poisoning, as well as others. This publication gives scientists a thorough evaluation of the biochemistry and biology, absorption, metabolic rate, biological activities, illness avoidance, as well as wellness promo of glutathione and also sulfur amino acids. Great Read. Cheers! 2 weeks ago By Gnome...
	Magnesium in health and disease By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	NATURAL ANTI-AGING MEDICINES
	Magnesium is an important mineral that is required for the development as well as the survival of people. Given that magnesium is a mineral and not synthesizable, it should be obtained through nutritional foods and/or supplements. Magnesium in Human Being Health and wellness and also Condition examines the advantages of magnesium supplements to reach suggested consumption as well as provides brand-new research study that recommends how reaching levels above the recommended intakes can promote health as well as deal with numerous conditions. Magnesium deficiency can trigger reduced lotion potassium as well as calcium levels, retention of sodium, and also low flowing degrees of governing hormonal agents. These changes in nutrients create neurological as well as muscle symptoms such as tremors as well as muscle spasms. Additional magnesium shortage creates anorexia nervosa, nausea or vomiting, throwing up, personality changes, and heart failure death. Causes of magnesium deficiency consist of alcoholic abuse, badly regulated diabetes mellitus, too much or persistent vomiting, and/or looseness of the bowels. Hence the results of inadequate and deficient intakes of magnesium degrees are vital to health and wellness and are examined by the professional clinicians in this publication. Magnesium in Human Being Wellness, as well as Condition, gives the most existing study to sustain the potential advantages or lack thereof for typical and high supplements with magnesium. Animal model research studies, as well as very early human trials, are reviewed to record various other disease states such as hypertension, cholesterol degree, kind 2 diabetes mellitus, as well as a cardiovascular disease that would benefit from increased magnesium. This was a good read. Cheers! 2 weeks ago By Gnome...
	The Vitamin D Solution - A 3-Step Strategy to Cure Our Most Common Health Problems by Michael F. Holick & Andrew Weil By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	SCIENCE & RESEARCH
	Vitamin D helps control the amount of calcium and also phosphate in the body.These nutrients are required to maintain bones, teeth, and also muscles healthy and balanced.Owing to food stronghold, diseases brought on by severe vitamin D shortage, such as rickets and osteomalacia, were practically eradicated in the United States by the very early 1900s. Nevertheless, inadequate sun exposure and persistent disease remain to cause vitamin D deficiency in all age groups.1 Vitamin D shortage (<20 ng/mL) and the deficiency (20-30 ng/mL) impact nearly 1 billion people worldwide.Besides the bone metabolic process, vitamin D has numerous roles in the body, including cell development inflection, neuromuscular and immune function, and inflammation reduction. It stays open to question; however, whether healthy and balanced levels of vitamin D can decrease the risk of non-skeletal diseases. The function of vitamin D in several sclerosis, autoimmune problems, infections, breathing disease, cardiometabolic condition, cancer cells, and also fracture threat is still being examined. In light of exactly how widespread it is, understanding who to test and when to deal with patients for vitamin D deficiency is necessary for health care doctors.As with lots of illness, evaluation and management of vitamin D deficiency need to follow osteopathic concepts, including the relationship of nutrition and lifestyle modifications with musculoskeletal health and the body's capacity to manage health and wellness when appropriate self-care is achieved. 2 weeks ago By Gnome...
	Health benefits of methylxanthines in disease - Medicine\\Pharmacology Bertil B. Fredholm By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	SCIENCE & RESEARCH
	Methylxanthines (MTXs) are taken in by nearly everyone in almost every location of the world. Caffeine, theophylline, and also theobromine are the most well‐known participants of this family of substances; they exist in coffee, tea, cacao, Yerba Mate', as well as soda pop beverages. MTXs are conveniently absorbed in the stomach tract and have the ability to permeate right into the central nervous system, where they put in substantial psychostimulant activities, which are more apparent in the intense intake. Coffee has actually been paradigmatic, as its use was prohibited in lots of diseases, however, this adverse view has actually radically transformed; evidence shows that MTXs show health advantages in illness involving cell death in the nerve system. This paper examines data that assess the preventative and also restorative potential of MTXs in a range of neurodegenerative conditions. Future viewpoints consist of using MTXs to advance the comprehending the pathophysiology of, inter alia, Alzheimer's and also Parkinson's disease(PD), as well as making use of the methylxanthine chemical moiety as a basis for the development of brand-new and also extra effective drugs. 2 weeks ago By Gnome...
	Molecular Nutrition - How dietary components modulate growth and promote health By Gnomebe 2 weeks ago \| Last Post: 2 weeks ago	SCIENCE & RESEARCH
	Molecular nutrition has become a new area in nutritional scientific research complying with both breakthroughs in molecular biology and also demands describing the microorganism's actions to nutrients at a molecular level. These include genetic expression, signal transduction, and also covalent alterations of healthy proteins (Müller and Kersten, 2003). Jacob and also Monod (1961) initially developed the lactose operon concept, which is the initial instance of genetics law by a nutrient. Shapiro et al. (1969) isolated pure lactose operon DNA from Escherichia coli, consequently completely showing the lactose operon design of Jacob as well as Monod (1961 ). Gene-nutrient interactions are the paradigm for the interplay between the genome as well as the environment. Every nutritional procedure counts on the interplay of a lot of proteins encoded by mRNA molecules that are shared in a provided cell. Changes of mRNA levels as well as in turn of the equivalent healthy protein levels (although the two variables do not necessarily change in parallel) are essential specifications in controlling the change of a nutrient or metabolite through a biochemical path. Thus, molecular nutrition assisted address essential concerns of wellness and also supplied beautiful mechanistic explanations of the cause and effect. Applications of "omics", such as genomics, transcriptome, proteome, as well as the metabolome, assisted in molecular nourishment understanding (Afman as well as Müller, 2006). For instance, Kitajka et al. (2004) examined the mind gene-expression adjustments in action to different polyunsaturated fatty acid (PUFA)-enriched diet regimens in rats making use of a high-density microarray. They found that PUFA-enriched diet regimens cause substantial changes in expression of a number of genetics in the main anxious cells, and these results appear to be primarily independent of their impacts on membrane make-up, helping with the understanding of the advantageous results of the ω-3 PUFA on the nervous system. Child et al. (2013) explored the device underlying boosted use of the amino acid glutamine to fuel anabolic procedures in pancreatic ductal adenocarcinoma (PDAC) cells utilizing metabonomics technology. They established that reprogramming of glutamine metabolic rate is mediated by oncogenic KRAS using the transcriptional upregulation and also suppression of essential metabolic enzymes in this path. Really good read. Cheers! 2 weeks ago By Gnome...
	Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury By Gnomebe 3 weeks ago \| Last Post: 3 weeks ago	SCIENCE & RESEARCH
	Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury Ronen Durst , Haim Danenberg , Ruth Gallily , Raphael Mechoulam , Keren Meir , … See all authors 01 DEC 2007 Abstract Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signalling. Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts. For the in vivo studies, the left anterior descending coronary artery was transiently ligated for 30 min, and the rats were treated for 7 days with CBD (5 mg/kg ip) or vehicle. Cardiac function was studied by echocardiography. Infarcts were examined morphometrically and histologically. For ex vivo evaluation, CBD was administered 24 and 1 h before the animals were killed, and hearts were harvested for physiological measurements. In vivo studies showed preservation of shortening fraction in CBD-treated animals: from 48 ± 8 to 39 ± 8% and from 44 ± 5 to 32 ± 9% in CBD-treated and control rats, respectively (n = 14, P < 0.05). Infarct size was reduced by 66% in CBD-treated animals, despite nearly identical areas at risk (9.6 ± 3.9 and 28.2 ± 7.0% in CBD and controls, respectively, P < 0.001) and granulation tissue proportion as assessed qualitatively. Infarcts in CBD-treated animals were associated with reduced myocardial inflammation and reduced IL-6 levels (254 ± 22 and 2,812 ± 500 pg/ml in CBD and control rats, respectively, P < 0.01). In isolated hearts, no significant difference in infarct size, left ventricular developed pressures during ischemia and reperfusion, or coronary flow could be detected between CBD-treated and control hearts. Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo. Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia. cannabinoids are natural and synthetic compounds structurally or pharmacologically related to the constituents of the plant Cannabis sativa or to the endogenous agonists (endocannabinoids) of the cannabinoid CB1 and CB2 receptors (for recent reviews see Refs. 17, 22, and 24). In a rat model, it was shown that anandamide, an endogenous cannabinoid (8), has a physiological triphasic effect on the cardiovascular system consisting of an initial reduction in heart rate (HR) and blood pressure followed by a brief pressor response and then a prominent reduction of blood pressure and HR (29). It has also been shown that endocannabinoids have a protective effect against myocardial ischemia and can help preserve coronary endothelial function during ischemia (15, 27, 28). These effects are receptor mediated and can be inhibited by specific CB1 and CB2 receptor blockers (15, 27, 28). In one study, a potent CB1 and CB2 receptor agonist, HU-210, was shown to substantially reduce the myocardial necrotic zone after left anterior descending coronary artery (LAD) ligation (28); in another trial, HU-210 was shown to significantly reduce the ischemic arrhythmic effect in treated animals. These effects were mediated by the CB2 receptor (15, 27). Other studies have shown that the cardioprotective effect of heat and ischemic preconditioning is mediated, partly at least, by CB2 receptors and can be abolished by CB2 receptor antagonists (3, 13). HU-210 was also shown to increase coronary blood flow and to be associated with the reduced remodelling in infarcted rat hearts (31, 32). These results indicate a possible role for the endocannabinoid system in stress-induced preconditioning. Cannabidiol (CBD) is a major cannabinoid constituent of Cannabis (18). In contrast to tetrahydrocannabinol, CBD binds very weakly to CB1 and CB2 receptors (18, 24). Contrary to most cannabinoids, CBD does not induce psychoactive or cognitive effects. CBD has been shown to have anti-inflammatory properties (6, 16, 33). CBD (together with tetrahydrocannabinol) has been successfully tested in a few preliminary human trials related to autoimmune diseases such as rheumatoid arthritis (2) and multiple sclerosis (4, 26, 38) and is well tolerated by humans (7, 18, 24). The mechanisms of action of CBD remain obscure. It has a mild effect on vanilloid VR1 receptors (1, 25). Recently, it was proposed that the anti-inflammatory effects of CBD might be mediated by enhancement of adenosine signalling through inhibition of its uptake (5). This effect apparently involves the adenosine A2A receptor (5). In view of the known cardioprotective effect of cannabinoids, the reduction in infarct size induced by adenosine receptor activation (34), the enhanced A2A receptor signalling by CBD (5), the anti-inflammatory effect of CBD, which might prevent immune-related myocardial injury (14), and its lack of psychotropic or cognitive effects (24), we studied the possible cardioprotective effect of CBD on ischemic rat hearts. We also tested whether any protective effect is exerted directly on the myocardium or via mediators of immune mechanisms. METHODS Animals. Male Sprague-Dawley rats (275–300 g body wt) were used: 7 animals were used in the CBD-treated and vehicle-injected arms of the Langendorff isolated rat heart model, and 14 animals were used in the CBD-treated and vehicle-injected arms of the whole animal study. The Institutional Animal Study Review Board approved the study. CBD. CBD was extracted from Cannabis resin (hashish) and purified as previously described (9). The crystalline CBD (66–67°C melting point) presented a single peak on gas chromatography analysis and is ≥99% pure (9). CBD was dissolved in absolute ethanol, with an equal volume of a detergent (Cremophor), and the solution was mixed until homogeneous. Saline was added to a final ratio of 1:1:18 ethanol-detergent-saline. The final concentration of 5 mg·kg body wt−1·day−1 was injected intraperitoneally. In vivo LAD ligation procedure. Rats were anesthetized with 10% ketamine-2% xylazine (0.85:0.15, 0.1 ml/kg im), intubated, and ventilated with a small animal respirator (Harvard). The heart was exposed via left sternotomy, and the LAD was reversibly occluded for 30 min with a snare fashioned from an encircling silk ligature and a section of 5-Fr feeding tube. Coronary occlusion and reperfusion were verified by visual inspection. After reperfusion, the released ligature was left in situ. The chest was closed in layers with uninterrupted sutures. Rats were extubated, lost body fluids were replaced by subcutaneous administration of 30–50 ml of saline, and the animals were treated with rymadil (5 mg/kg ip) analgesia for 3 days. The animals were randomized to receive intraperitoneal injections of 5 mg/kg CBD or solvent vehicle as control 1 h before the procedure and every 24 h thereafter for 7 days until they were killed. The drug and vehicle solutions were prepared in separate laboratories to ensure that the staff (e.g., echocardiography and pathology) was blinded to the treatment arm. After 7 days, animals were reanesthetized and ventilated as described above. The LAD was permanently reoccluded, and the heart was harvested for further analysis. Ex vivo isolated Langendorff rat heart LAD ligation. To assess the direct CBD effect on the heart, we used the isolated Langendorff rat heart model (19). Animals were intraperitoneally injected with 5 mg/kg CBD or solvent 24 and 1 h before heart removal. At 30 min before heart removal, unfractionated heparin (750 IU, 0.15 ml ip) was injected into the rat. Animals were anesthetized with 0.6–0.8 ml of 20% pentobarbital sodium by intraperitoneal injection. After it was removed, the heart was placed in cold (4°C) saline-heparin solution (100 ml of saline and 750 IU of heparin). The aorta was cannulated, and the heart was perfused with modified Krebs-Henseleit solution under a constant pressure of 90 mmHg. A water-filled latex balloon was inserted into the left ventricular (LV) cavity via the left atrium, coupled to a pressure transducer, to record LV developed pressures (LVDP). A 50-μl Hamilton syringe was used to adjust LV end-diastolic pressure (LVEDP) to 5–10 mmHg. Coronary flow (CF) was measured throughout the procedure by collection of the effluent. HR was set to 300 beats/min by an external pacemaker attached to the left auricle to adjust for possible differences in HR between the treatment groups. LVDP was continuously recorded on a polygraph. After 30 min of stabilization, a 4-0 silk suture was placed under the LAD below an imaginary interauricular line and then threaded through a buttonlike snare. This allows ligation for a prolonged period without harm to the heart. The LAD was occluded for 45 min; then the snare was released, and reperfusion through the LAD was allowed for 45 min. After 45 min of reperfusion, the LAD was reoccluded and the percent infarct size of the area at risk was determined (see below). Echocardiography. Echocardiographic imaging was performed using a GE Vivid3 platform equipped with a 13-MHz linear epiaortic transducer (General Electric, Haifa, Israel). The probe was positioned in a left parasternal position, and two-dimensional imaging of the heart in the short axis was performed using a high frame rate. This image was used to guide an M-mode cursor down the medial axis of the LV. Measurements were performed in triplicate using the leading edge convention for myocardial borders. The images were acquired with HR at 250–350 beats/min. The following parameters were measured: LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD). Shortening fraction (SF) was calculated using these variables. Infarct size measurements and histopathology. Measurements were performed as previously described (20, 21, 37). Briefly, 0.5–1 ml of 1% Evans blue solution in saline was slowly infused retrogradely through the aorta into the coronary arteries to mark the area at risk (not stained). The heart was then frozen (−20°C) for 1 h in aluminum foil and cut into 2-mm-thick transverse sections from the occlusion area (LAD) to the apex (usually 4–6 slices). The slices were stained by incubation at 37°C for 15 min in 1% (wt/vol) triphenyltetrazolium chloride (TTC) in phosphate buffer (pH 7.4) and fixed in 10% (vol/vol) formaldehyde solution. The stained slices were photographed, and the area of LV at risk and the area of infarcted tissue in the risk zone were determined by planimetry using Adobe Photoshop software. Subsequently, tissue slices were fixed in 5% ammonium hydrochloride, embedded in paraffin, cut into 5-μm sections, and stained with hematoxylin and eosin and Masson's trichrome. The extent of the inflammatory response was graded on a scale of 1–3 by an experienced pathologist who was blinded to the treatment groups. Serum TNF-α, IL-6, and C-reactive protein measurements. Rats were bled 7 days after coronary ligation. Sera were separated and frozen. Concentration of TNF-α, Il-6, and C-reactive protein (CRP) in the sera was measured by commercial ELISA kit according to the manufacturer's protocols. ELISA reagents for TNF-α were purchased from Biosource (Camarillo, CA), for IL-6 from AbD Serotec (Kidlington, UK) and Prospect (Rehovot, Israel), and for CRP from Immunology Consultants Laboratory (Newberg, OR). Statistical analysis. Unpaired Student's t-test was used to compare baseline data between groups. Within-group outcomes were compared with baseline using paired t-test analysis. Between-group outcome analysis was performed using percent change from baseline and unpaired t-test. Linear correlation was used to compare infarct size and ejection fraction (EF). RESULTS Fourteen CBD- or vehicle-treated animals completed the experimental design. Four control animals and three CBD-treated animals died before day 7. Weight, LVEDD, LVESD, and SF of the animals that survived to day 7 are presented in Table 1. Table 1. Baseline and 7-day parameters of CBD and control animals Enlarge table All animals showed significant weight loss 7 days after the procedure: from 326.8 ± 3.4 g at baseline to 314.6 ± 8.7 g (CBD) and from 326.1 ± 4.3 g at baseline to 319.7 ± 8.1 g (controls; P < 0.05). As expected, a significant reduction in SF was observed in all animals after LAD ligation: from 48 ± 8% at baseline to 39 ± 8% (CBD) and from 44 ± 6% at baseline to 32 ± 9% (controls; P < 0.05). The LV area at risk and infarct size as a percentage of area at risk are presented in Fig. 1. The area at risk was similar in CBD and control animals. However, the mean infarct size was significantly and remarkably reduced in CBD-treated animals (9.6 ± 3.9% vs. 28.2 ± 7.0% in CBD and control arms, respectively, P < 0.001). Thus a relative reduction of 66% in the infarcted zone was observed in the CBD-treated animals. The ejection fraction on day 7 negatively correlated with infarct size (R2 = 0.45, β = −0.9; Fig. 2). To further determine whether the reduction in infarct size is related to an improved remodeling process, LV function of animals with the largest infarct in the CBD group was compared with that of animals at the lower end of infarct size range in the control groups. In these animals, the area of the infarct ranged from 16 to 20% in both groups. There was no difference in LVEDD on day 7 (7.4 ± 0.8 vs. 7 ± 0.6 mm respectively) or in SF (33% vs. 37% respectively) between CBD-treated animals and controls. Although this comparison is not statistically powerful, it might suggest that the CBD effect is mainly due to the reduction in infarct size, rather than major changes in myocardial contractility or remodeling processes. Fig. 1.A: percent area at risk of the left ventricle (LV) and percent infarct size of the area at risk in cannabidiol (CBD)-treated and control animals. Infarct size was measured as percentage of area at risk by planimetry using triphenyltetrazolium chloride (TTC) staining. Animals were treated with CBD (5 mg/kg) 1 h before and 7 days after ligation of the left anterior descending coronary artery or were untreated. P < 0.01, CBD vs. control (by unpaired 2-tailed t-test). B and C: TTC staining in a CBD and a control animal, respectively. Area at risk is stained red and infarct is white. Download figureDownload PowerPoint Fig. 2.Correlation between infarct size and ejection fraction (EF). ⧫, CBD; ○, control. R2 = 0.45 (P < 0.05), β = −0.9. Dashed line represents estimated linear correlation. Download figureDownload PowerPoint Hearts from each group were stained with hematoxylin and eosin and Masson's trichrome (Fig. 3). The inflammatory infiltrate was graded on a scale of 1–3 by an expert pathologist on the basis of the number of leukocytes infiltrating the border of the infarcted zone. The inflammatory response in the control animals was graded 2–3 compared with 1+ or 0 in the CBD-treated animals (Fig. 3, A and B), indicating elimination of the inflammatory process in the treated animals. However, granulation tissue formation with early collagen deposition was similar in the treated and control animals (Fig. 3, D and E). Fig. 3.Histological analysis of CBD-treated and control rats. A: marked mononuclear infiltration (arrows) and early collagen fiber deposition in a typical control animal. Magnification ×40, hematoxylin and eosin. B: almost total lack of inflammation in an animal treated with CBD. Note occasional mononuclear cells (arrows) in viable myocardial interstitium and marked edema (arrowhead). Magnification ×40, hematoxylin and eosin. C: early collagen deposition in infarcted area in a control animal. Magnification ×40, Masson's trichrome. D: early collagen deposition in infarcted area in a CBD-treated animal. Staining was similar in CBD and control groups. Magnification ×40, Masson's trichrome. E: replacement of necrotic tissue by early fibrovascular granulation tissue in a control heart; findings were identical in CBD-treated hearts (data not shown). Magnification ×20, Masson's trichrome. Download figureDownload PowerPoint To understand whether the CBD cardioprotective effect is due to a direct effect on the myocardium or, rather, is mediated via secondary mechanisms, in vitro isolated heart studies were performed. Infarct size, area at risk, LVDP, and coronary flow (CF) after coronary ligation, presented as percentage of the baseline values after stabilization, are shown in Table 2. No differences in any of the parameters were observed between CBD-treated and control animals. Table 2. Infarct size and LVDP as percentage of baseline during ischemia and after reperfusion in CBD and control animals in an isolated heart preparation Enlarge table In view of the lack of CBD effect on isolated heart, IL-6, CRP, and TNF-α were measured on day 7 (Table 3). IL-6 was significantly lower in the sera of CBD-treated than control animals (254 ± 22 vs. 2,812 ± 500 pg/ml, P < 0.001). CRP and TNF-α did not differ significantly between the two groups on day 7. Table 3. TNF-α, IL-6, and CRP in sera of CBD and control aniimals Enlarge table DISCUSSION Our study demonstrates that CBD has a significant in vivo cardioprotective effect against myocardial ischemia induced by LAD ligation, with reduction of infarct size measured as percentage of the area at risk by TTC staining. This was accompanied by a significant reduction in the decrease in LV function, which is observed after coronary occlusion, measured by echocardiography (Fig. 4). The EF after 7 days correlated pretty well with infarct size, indicating that the preservation of EF in treated animals is mainly due to reduced infarct size. This fact is further supported by comparing animals with similar infarct sizes from both groups. Fig. 4.A: CBD-treated animal with preserved LV function and preserved motion of the anterior wall (horizontal arrow) and a corresponding shortening fraction (SF) of 45%. B: M-mode echocardiography of a sham-treated rat with reduced SF and reduced motion of the anterior wall (horizontal arrow) and a corresponding SF of 31%. Double-headed arrows: LV end-diastolic diameter (a) and LV end-systolic diameter (b). IVSd, interventricular septum thickness at diastole; LVIDs and LVIDd, LV internal diameter at systole and diastole, respectively; LVPWd, LV posterior wall thickness at diastole. Download figureDownload PowerPoint The reduction of the infarct size was associated with a qualitative reduction in inflammatory infiltration of the ischemic and necrotic myocardial zones. CBD did not affect early collagen formation as detected by Masson's trichrome staining. These findings were associated with a significant reduction in serum IL-6 levels. We did not detect a significant effect of CBD on infarct size, cardiac contractility, and coronary blood flow in the in vitro isolated rat heart model. Because CBD has known anti-inflammatory effects (5, 6), it is plausible that the in vivo cardioprotective effect of CBD may be mediated by a systemic immunomodulatory effect, such as the reduction in IL-6 levels. A similar concept was recently proposed as the mechanism of action of a newly synthesized molecule, 1,6-bis(phosphocholine)-hexane, which binds to CRP and prevents its interaction with various inflammatory ligands. Complement activation was also noted (23). Infarct size is reduced from 24% in CRP-treated rats 5 days after LAD ligation to 17% by 1,6-bis(phosphocholine)-hexane (23). CRP is assumed to play a role in the innate immunity and immune activation in damaged myocardium (14). Thus anti-inflammatory agents such as CBD and 1,6-bis(phosphocholine)-hexane might have a role in preventing immune-related myocardial injury. It should be stressed that the in vivo and in vitro models were not fully comparable. The CBD treatment duration and the reperfusion period were shorter in the isolated heart model. Also, the ischemic period was longer. These experimental differences may explain the difference in infarct size between the in vivo and ex vivo experiments. However, the CBD effect in vivo was very robust, whereas it was essentially nonexistent in the ex vivo experiment (Table 2), indicating that CBD did not have an equivalent effect in vivo and ex vivo. Previous studies have shown that cannabinoids, which act on cannabinoid receptors, reduce infarct size and protect the heart from ischemia-related arrhythmia (15, 27, 28). Also endogenous cannabinoids were found to be involved in preconditioning induced by heat and ischemia. Furthermore, such cannabinoids have vasodilatory effects and can improve endothelial function (3, 13). In all these studies, however, the effects of these cannabinoids, either endogenous or synthetic, were shown to be mediated by activation of the CB1 or CB2 receptor. Inasmuch as CBD does not act via the known cannabinoid receptors and does not have direct hemodynamic effects, its mechanism of action presumably differs from that of the cannabinoid receptor agonists. Evidence of transactivation of adenosine receptors by CBD was recently published (5). This effect was associated with the anti-inflammatory properties of CBD. Adenosine receptors seem to play a role in protecting the heart (34). Adenosine A1 and A3 receptors have been most intensively studied, and the A2A receptor may also play a role. The A3 receptor seems to have multiple beneficial effects on ischemia-reperfusion injury, including modulation of necrotic and apoptotic cell death and enhancement of contractile function (11). A1 receptor overexpression increases myocardial resistance to ischemia (12). The A2A receptor may also play a role in protection from ischemia (34–36). In view of the recently proposed mechanism of action of CBD associating it with enhancement of adenosine signaling (5), one might speculate that the effect on the myocardium may be mediated via adenosine receptor effects. In the past, corticosteroids were studied as a potential therapy for myocardial infarction because of their anti-inflammatory effect (10). However, this therapy has ultimately turned out to be harmful, inasmuch as corticosteroids delay and interfere with myocardial scar formation. This leads to thinner scars and increases susceptibility to rupture (30). In our experiments, we observed the treated animals for 7 days only. Thus it is possible that the beneficial effect observed after 7 days may become harmful over a longer time period. It might cause a delay in scar healing and also might reduce scar strength, leading to unfavorable LV remodeling in a manner similar to that of corticosteroids. Therefore, in CBD-treated animals, a longer period of follow-up is warranted to assess the long-term recovery and safety. However, we did not find any difference between the treated and control animals in relation to myofibroblast activity. This might suggest that CBD did not adversely affect the scarring process. In our trial, we have shown that CBD induces a reduction in infarct size that is correlated with EF, is caused by reduced myocardial inflammation, and is not associated with favorable remodeling processes. We therefore assume that the reduced inflammatory response is mediated by an attenuated immunologic response. This is in agreement with other trials that have shown beneficial effects of CBD in a number of inflammatory diseases (2, 4, 6, 26, 33). However, we have yet to establish the precise inflammatory mechanism affected by CBD. In conclusion, we have shown that CBD causes reduced infarct size in an in vivo rat model of ischemia and reperfusion. Furthermore, it seems that this effect is not direct and may be mediated by a reduced inflammatory response. Thus CBD may be a promising novel treatment for myocardial ischemia. FOOTNOTES The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. We thank Dr. Eli Pikarsky (Pathology Department, Hadassah Hebrew University Medical Center) and Dr. Marielle Scherrer-Crosbie (Massachusetts General Hospital Echo Lab) for advice and Dr. Oren Shibolet (Gastroenterology Department, Hadassah Hebrew University Medical Center) for technical assistance. AUTHOR NOTES Address for reprint requests and other correspondence: R. Durst, Cardiac Echo Lab, Massachusetts General Hospital, Blake 2, Rm. 255, 55 Fruit St., Boston, MA 02114 (e-mail: rdurst@partners.org) 3 weeks ago By Gnome...
	Otto Warburg's contributions to current concepts of cancer metabolism By Gnomebe 3 weeks ago \| Last Post: 3 weeks ago	SCIENCE & RESEARCH
	Otto Warburg spearheaded quantitative investigations of cancer cells metabolic rates, as well as photosynthesis as well as respiration. Warburg and colleagues displayed in the 1920s that, under cardio conditions, tumour cells metabolize roughly significantly much more glucose to lactate in an offered time than regular tissues, a sensation called the Warburg result. Nevertheless, this increase in aerobic glycolysis in cancer cells is often mistakenly believed to occur rather than mitochondrial respiration and has been misinterpreted as proof for damage to respiration instead of damages to the regulation of glycolysis. As a matter of fact, numerous cancers cells show the Warburg impact while retaining mitochondrial respiration. We re-examine Warburg's monitorings in regard to the existing ideas of cancer cells metabolic process as being intimately linked to changes of mitochondrial DNA, oncogenes and tumour suppressors, and also hence easily exploitable for cancer therapy. Otto Warburg’s contributions to current concepts of cancer metabolismWillem H. Koppenol, Patricia L. Bounds and Chi V. Dang‡ Please register here. 3 weeks ago By Gnome...

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