Ketamine is the first truly new pharmacological approach to treating depression in the past 50 years and could herald a new generation of rapid acting antidepressants, researchers have predicted.
“We haven’t had anything really new for about 50 or 60 years,” said Allan Young, professor of mood disorders at the Institute of Psychiatry, Psychology and Neuroscience at King’s College, London, at a briefing on 12 July at London’s Science Media Centre.
Most of the new launches have been “tinkering with drugs which were really discovered in the ’50s and ’60s,” he explained. “Even the famous Prozac, which came in in the late ’80s, is really just a refinement of the tricyclic antidepressants that came in the ’50s. People say we are still in the age of steam, and we need to go to the next technological advance.”
In the past few years the focus has fallen on ketamine, which is used for pain relief and anaesthesia but is better known for being a horse sedative and a “club drug” that can induce hallucinations and calmness. It has been found to have rapid antidepressant effects and to be effective in many patients with treatment resistant depression.
US clinics increasingly offer IV infusions of ketamine off label, and in March esketamine, a nasal ketamine based drug, was approved by the US Food and Drug Administration for treatment resistant depression,1 at a cost of £32 400 (€36 060; $40 615) per patient per year.
Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the US National Institute of Mental Health, who has been a key figure in the discovery and evaluation of ketamine as an antidepressant, said that one of the main problems with current antidepressants was their speed of onset in terms of antidepressant and anti-suicidal effects.
He explained that it took 10-14 weeks to see significant improvement with monoaminergic based antidepressants. “In my mind that is too slow,” he said. “We are focusing on treatments that can produce results within hours. That is where we are heading with the next generation of antidepressant, and ketamine is now the prototype for future generation antidepressants which will have rapid, robust antidepressant effects—rapid within a few hours.”
Efficacy and tolerability
Zarate said that, besides correcting chemical imbalances of serotonin and norepinephrine, the new generation of ketamine based antidepressants had other effects such as enhancing plasticity and restoring the synapses and dendrite circuits that shrivel in depression.
When ketamine is given to patients it binds to the N-methyl-D-aspartate (NMDA) receptor, causing a series of transient side effects including decreased awareness of the environment, vivid dreams, and problems in communicating. But the half life of ketamine is only two to three hours, so these side effects quickly subside, whereas the therapeutic effects of the drug last seven days or longer.
Zarate’s team is now focusing on the 24 metabolites of ketamine to hone the drug’s efficacy and tolerability. One of these, hydroxynorketamine, has already been shown to have similar antidepressive effects to ketamine in animals, without the side effects, and it is due to be tested in patients this autumn.
“Ketamine may actually be a prodrug for hydroxynorketamine,” said Zarate.
A few dozen patients with treatment resistant depression have been treated with ketamine in UK trials, and the European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency are due to reach a decision on authorising esketamine for marketing in October. If the drug is approved private clinics will be able to provide it. But it would be unlikely to be available through the NHS until at least 2020, if at all, as the National Institute for Health and Care Excellence would need to deem it cost effective.
Rupert McShane, consultant psychiatrist and associate professor at the University of Oxford, said that, as well as the likely high cost of esketamine, patients treated with it must be observed in a clinic for two hours after each administration. This would require substantial clinical time, as esketamine is given twice a week for the first month, once a week for the second month, and once a week or once a fortnight from then on.
McShane also recommended that, if approved, a multidrug registry should be set up to monitor the long term safety and effectiveness of ketamine based drugs. Patients would be asked to input their use of any prescribed ketamine, esketamine, or any other future ketamine based product, as well as any self medication with illicit ketamine.
A review of large-scale studies involving more than 1.5 million people found all-cause mortality is higher for those who eat meat, particularly red or processed meat, on a daily basis. Conducted by physicians from Mayo Clinic in Arizona, “Is Meat Killing Us?” Is Meat Killing Us PDF
The authors analyzed six studies that evaluated the effects of meat and vegetarian diets on mortality with a goal of giving primary care physicians evidence-based guidance. The data found the steepest rise in mortality at the smallest increases of intake of total red meat. That 2014 study followed more than one million people over 5.5 to 28 years and considered the association of processed meat (such as bacon, sausage, salami, hot dogs and ham), as well as unprocessed red meat (including uncured, unsalted beef, pork, lamb or game). Results: Physicians should advise patients to limit animal products when possible and consume more plants than meat. They also found a 3.6-year increase in life expectancy for those on a vegetarian diet for more than 17 years, as compared to short-term vegetarians.
Carcinogenicity of consumption of red and processed meat << After thoroughly reviewing the accumulated scientific literature, a Working Group of 22 experts from 10 countries, based on limited evidence felt that the consumption of red meat causes cancer in humans and strong mechanistic evidence supporting a carcinogenic effect. Processed meat was classified as carcinogenic to humans (Group 1), based on sufficient evidence in humans that the consumption of processed meat causes colorectal cancer. The experts concluded that each 50 gram portion of processed meat eaten daily increases the risk of colorectal cancer by 18%.
Red meat refers to unprocessed mammalian muscle meat—for example, beef, veal, pork, lamb, mutton, horse, or goat meat—including minced or frozen meat; it is usually consumed cooked. Processed meat refers to meat that has been transformed through salting, curing, fermentation, smoking, or other processes to enhance fl avour or improve preservation. Most processed meats contain pork or beef, but might also contain other red meats, poultry, off al (eg, liver), or meat byproducts such as blood. Meat processing, such as curing and smoking, can result in formation of carcinogenic chemicals, including N-nitroso-compounds (NOC) and polycyclic aromatic hydrocarbons (PAH). Cooking improves the digestibility and palatability of meat, but can also produce known or suspected carcinogens, including heterocyclic aromatic amines (HAA) and PAH. High-temperature cooking by panfrying, grilling, or barbecuing generally produces the highest amounts of these chemicals. << Factors affecting heterocyclic aromatic content in meat
The largest body of epidemiological data concerned colorectal cancer. Data on the association of red meat consumption with colorectal cancer were available from 14 cohort studies. < Meat, fish, and colorectal cancer risk_ the European Prospective Investigation into cancer and nutrition < [ Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [<20 g/day] intake, HR = 1.35, 95% CI = 0.96 to 1.88; Ptrend = .03) and inversely associated with intake of fish (>80 g/day versus <10 g/day, HR = 0.69, 95 % CI = 0.54 to 0.88; Ptrend<.001), but was not related to poultry intake] Also Red Meat, Chicken, and Fish Consumption and Risk of Colorectal Cancer <<Conclusion: Consumption of fresh red meat and processed meat seemed to be associated with an increased risk of rectal cancer. Consumption of chicken and fish did not increase risk.
In a huge study of half a million men and women, researchers have demonstrated an association between processed meat and cardiovascular disease and cancer. Meat consumption and mortality – results from EPIC <<< Often vegetarians have healthier lifestyles than the general population, they are less likely to smoke, are less fat, and are more likely to be physically active. This EPIC (European Prospective Investigation into Cancer and Nutrition) study involved ten countries and 23 centres in Europe and almost half a million people. In general a diet high in processed meat was linked to other unhealthy choices. Men and women who ate the most processed meat ate the fewest fruit and vegetables and were more likely to smoke. Men who ate a lot of meat also tended to have a high alcohol consumption. A person’s risk of premature death (increased risk of all cause mortality) increased with the amount of processed meat eaten. This is also true after correcting for confounding variables. It is estimated that 3% of premature deaths each year could be prevented if people ate less than 20g processed meat per day.
Men who regularly eat moderate amounts of processed red meat such as cold cuts (ham/salami) and sausage may have an increased risk of heart failure incidence and a greater risk of death from heart failure. <<Processed and Unprocessed Red Meat Consumption and Risk of Heart Failure << — Processed meats are preserved by smoking, curing, salting or adding preservatives. Examples include cold cuts (ham, salami), sausage, bacon and hot dogs. Processed red meat commonly contains sodium, nitrates, phosphates and other food additives, and smoked and grilled meats also contain polycyclic aromatic hydrocarbons, all of which may contribute to the increased heart failure risk, The Cohort of Swedish Men study — the first to examine the effects of processed red meat separately from unprocessed red meat — included 37,035 men 45-79 years old with no history of heart failure, ischemic heart disease or cancer. Men who ate the most processed red meat (75 grams per day or more) had a 28 percent higher risk of heart failure compared to men who ate the least (25 grams per day or less) after adjusting for multiple lifestyle variables. Men who ate the most processed red meat had more than a 2-fold increased risk of death from heart failure compared to men in the lowest category. For each 50 gram (e.g. 1-2 slices of ham) increase in daily consumption of processed meat, the risk of heart failure incidence increased by 8 percent and the risk of death from heart failure by 38 percent.
Red Meat Consumption and Mortality <<Conclusions: Red meat consumption is associated with an increased risk of total, CVD, and cancer mortality. Substitution of other healthy protein sources for red meat is associated with a lower mortality risk. We estimated that substitutions of 1 serving per day of other foods (including fish, poultry, nuts, legumes, low-fat dairy, and whole grains) for 1 serving per day of red meat were associated with a 7% to 19% lower mortality risk. We also estimated that 9.3% of deaths in men and 7.6% in women in these cohorts could be prevented at the end of follow-up if all the individuals consumed fewer than 0.5 servings per day (approximately 42 g/d) of red meat.
Vegetarian diets, low-meat diets and health a reviewBoth vegetarian diets and prudent diets allowing small amounts of red meat are associated with reduced risk of diseases, particularly CHD and type 2 diabetes. There is limited evidence of an association between vegetarian diets and cancer prevention. Evidence linking red meat intake, particularly processed meat, and increased risk of CHD, cancer and type 2 diabetes is convincing and provides indirect support for consumption of a plant-based diet.
Food sources of nitrates and nitrites the physiologic context for potential health benefits. —Approximately 80% of dietary nitrates are derived from vegetable consumption; sources of nitrites include vegetables, fruit, and processed meats. Nitrites are produced endogenously through the oxidation of nitric oxide and through a reduction of nitrate by commensal bacteria in the mouth and gastrointestinal tract. As such, the dietary provision of nitrates and nitrites from vegetables and fruit may contribute to the blood pressure–lowering effects of the Dietary Approaches to Stop Hypertension (DASH) diet. We quantified nitrate and nitrite concentrations by HPLC in a convenience sample of foods. Incorporating these values into 2 hypothetical dietary patterns that emphasize high-nitrate or low-nitrate vegetable and fruit choices based on the DASH diet, we found that nitrate concentrations in these 2 patterns vary from 174 to 1222 mg. The hypothetical high-nitrate DASH diet pattern exceeds the World Health Organization’s Acceptable Daily Intake for nitrate by 550% for a 60-kg adult. These data call into question the rationale for recommendations to limit nitrate and nitrite consumption from plant foods; a comprehensive reevaluation of the health effects of food sources of nitrates and nitrites is appropriate. The strength of the evidence linking the consumption of nitrate- and nitrite-containing plant foods to beneficial health effects supports the consideration of these compounds as nutrients.
Nitrate-containing beetroot enhances myocyte metabolism and mitochondrial content < The goodness of plants! Cells treated with beetroot exhibited significantly increased oxidative metabolism, concurrently with elevated metabolic gene expression including peroxisome proliferator-activated receptor gamma coactivator-1 alpha, nuclear respiratory factor 1, mitochondrial transcription factor A, and glucose transporter 4, leading to increased mitochondrial biogenesis. Our data show that treatment with a beetroot supplement increases basal oxidative metabolism. Our observations are also among the first to demonstrate that beetroot extract is an inducer of metabolic gene expression and mitochondrial biogenesis. These observations support the need for further investigation into the therapeutic and pharmacological effects of nitrate-containing supplements for health and athletic benefits.
Everyone knows about CoQ10, with many people frequently taking it for ‘vascular health’ . It is true that ubiquinol in the blood stream is an anti-oxidant that helps maintain vascular integrity. Ubiquinol–10 is an endogenously synthesized lipid antioxidant that scavenges free radicals and is involved in a-tocopherol homeostasis. It prevents lipid peroxidation and in the process is oxidized to ubiquinone.
95 % of the quinone is maintained as ubiquinol, which must be regenerated from ubiquinone after it prevents lipid oxidation.
The study below demonstrated derivatives of chlorophyll can catalyze the reduction of ubiquinone to generate ubiquinol in plasma. The chlorophyll in our system is obtained from green leafy vegetables, and it is derivatives of the chlorophyll that may be catalyzing the reforming of ubiquinol, rather than ascorbic acid, carotenoid, tocopherol and flavonoid antioxidants that are usually given the credit for this process.
In the blood stream, metabolites of chlorophyll , such as chlorophyllide a, pheophytin-a, pheophorbide-a, methyl pheophorbide-a, 10-OH-pheophorbide-a, 10- OH-methyl pheophorbide-a, pyro pheophorbide-a and methyl pyropheophorbide are formed and may catalyze the photoreduction of ubiquinone to ubiquinol.
Both light and light-absorbing chlorophyll metabolites can be present in capillaries, arteries and veins of several animals including humans. If chlorophyll metabolites catalyze the photoreduction of plasma ubiquinol in vivo, it would be a novel mechanism to maintain high levels of plasma ubiquinol – and this is what the paper listed in it’s research proposes, is that light through our skin drives chlorophyl metabolites to regenerate the phytonutrient ubiquinol.
Consumption of fruits and vegetables was inversely associated with stroke incidence, stroke mortality, ischemic heart disease mortality, and CVD mortality.
Known modifiable risk factors for CVD include smoking, sedentary lifestyle, diet, dyslipidemia, hypertension, obesity, and type 2 diabetes.
The observed protective effect of consuming plant foods on chronic diseases is likely due to their bioactive components.
Phytosterols are naturally-occurring plant sterols found in the non-saponifiable fraction of plant oils. Plants synthesize several types of phytosterols (e.g., sterols and stanols) that are structurally similar to cholesterol, except for the functional group substitutions on the sterol side chain at the C24 position. Beta-sitosterol (most abundant), campesterol, and stigmasterol comprise almost our entire intake of phytosterols. Since humans do not synthesize phytosterols, they must be obtained from the diet. The main dietary sources of naturally-occurring phytosterols are vegetable oils, nuts, grains and, to a lesser extent, fruits and vegetables. Commonly consumed products that are fortified with phytosterols, such as Benecol™ and Take Control™ are found in many foods. . Benecol spread contains stanol esters derived from tall oil (pine tree wood pulp) and Take Control margarine contains sterol esters from soybeans. Consuming 2–3 g/d of phytosterols from these products resulted in approximately 14% reduction in LDL with no change in HDL. Thus, both sterols and stanols are equally effective in lowering LDL concentration. NCEP ATP 111 guuidelines: two grams of plant sterol or stanol esters daily for optimal dietary therapy for elevated LDL.
Flavonoids: The most common flavonoids are flavones, flavanols, catechins, and anthocyanins, along with anthoxanthins. There is an inverse relationship between flavonoid intake and chronic diseases including CVD. Red wines contain an abundance of polyphenols including phenolic acids (for example, gallic acid, and caffeic acid), stilbenes (resveratrol), and flavonoids (for example, catechin, epicatechin, quercetin, rutin) . Gallic acid has more antioxidant activity than caffeic acid. Wine polyphenols can induce vasorelaxation via nitric oxide synthesis , decrease platlet aggregation, and decrease inflammatory mediators. Resveratrol is a polyphenol found principally in the skin of grapes and, in lesser amounts, in peanuts. It inhibits both LDL oxidation and platelet aggregation and scavanges free radicals.
Lignans: Lignans are polyphenols found in plants, especially in flaxseed (secoisolariciresinol diglucoside), sesame seeds (sesamin, sesamolin), and soy, followed by whole-grains cereals (syringaresinol), and legumes, including nuts. Fruits and vegetables contain a wide variety of lignans (e.g., matairesinol (MAT), pinoresinol (PINO) and lariciresinol (LARI)) but in minute quantities. The proposed mechanisms by which dietary lignans could reduce the risk of CVD include the phytoestrogenic, and antioxidant activity of these compounds and their metabolites. Some plant lignans such as matairesinol (MAT), secoisolariciresinol (SECO), pinoresinol (PINO), and lariciresinol (LARI) are metabolized by intestinal bacteria to enterolignans (enterodiol and enterolactone) in various proportions.
Resistant starches: Complex carbohydrates derived from starch contribute over half of humans’ daily energy requirements. Starch is a homopolysaccharide made in plants and stored in granules. Amylose and amylopectin are two polymers found in starch and are identified based on the glycosidic bond linking the α-D-glucose monomers. Amylose is a linear polymer with α-(1,4) linkages while amylopectin has linear α-(1,4) linkages and α-(1,6) branch points. There are four types of resistant starches – types one to four. Dietary sources of RS 1 include partially milled grains and seeds. RS 2 can be found in raw potatoes, legumes, just-ripe bananas, and high-amylose maize (HAM). RS 3 results from retrograded foods, such as potatoes, cereals, and breads. Chemically- or physically-modified starch and resistant maltodextrins are known as RS 4 and 5, respectively. Due to lack of enzymatic hydrolysis, the direct contribution of glucose to blood from RS is minimal and allows for an attenuated post-prandial glycemic response. Peripheral insulin sensitivity (Si) also improved by approximately 20% in individuals with metabolic syndrome consuming the same amount or RS. There is production of short chain fatty acids (SCFA) from RS fermentation by gut microbiota in the large intestine which tereby makes RS bioactive. The SCFA are capable of influencing risk, and even treatment, of NCDs such as diabetes and cancer through several mechanisms: decreasing luminal pH, enhancing mineral absorption, and stimulating the release of two satiety peptides known as glucagon-like peptide -1 (GLP-1) and peptide tyrosine tyrosine (PYY) to the periphery . RS can act as a prebiotic to selectively increase the concentration and viability of certain bacteria, such as Ruminococcus bromii .Intra-individual variation in gut microbiota may influence RS fermentation, the production of SCFA, and upregulation of GLP-1.
Cyclic Dipeptides: Cyclic dipeptides (also known as 2,5dioxopiperazines; 2,5-diketopiperazines; cyclo (dipeptides); or dipeptide anhydrides) are relatively simple compounds and, therefore, are among the most common peptide derivatives found in nature. Consistent with a role for fermentation process in synthesis of cyclic dipeptides is the observation of high levels of cyclo (His-Pro) in foods that undergo fermentation and/or high heat treatment of protein-rich foods. Such examples are nutritional supplements (e.g., TwoCal HN and Jevity), milk, yogurt, sauces, and fermented fish . Active cyclic dipeptides include cyclo (His-Pro), cyclo (Leu-Gly), cyclo (Tyr-Arg), and cyclo (Asp-Pro). Of these only cyclo (his-Pro)[CHP] has been shown to be endogenous to animal kingdom. CHP may act as an appetite suppressant and satiety-inducer. There is a possible role of CHP in insulin secretion and glucose metabolism. CHP causes higher insulin excursions without any change in C-peptide suggesting that CHP may decrease hepatic insulin clearance. Items with CHP include tuna, fish sauce, Dried Shrimp , Spent Brewer’s Yeast hydrolysate, and others.
Fruit Berries: Polyphenols found in berries and other plant foods are particularly associated with anti-inflammatory, antioxidant, cardioprotective, and chemopreventive properties. Several compounds contribute to the antioxidant properties of berries and are typically found in the outer parts of the fruit or berry, most often as cinnamic and/or benzoic acid derivatives. Tanins, Anthocyanins, carotenoids and stilbenes such as resveratrol are present in berries. Some amounts of resveratrol can be found in cranberries, strawberries, and other berries. Chokeberry, bilberry, and blackcurrant berries have the highest antioxidant capacity of the different berry fruits (umol Trolox/g fresh weight), and whole fruit extracts have greater antioxidant activity than many isolated phenolic compounds or vitamins . Strawberries are known to be high in phenolic compounds such as the phenolic acid derivative ellagic acid, and contain a significant amount of vitamin C. Blueberries are noted for a wide variety of anthocyanin compounds, while both cranberries and blueberries also contain significant concentrations of phenolic acids. Anti-oxidants in Berries provide anti-inflammatory activity, free radical scavenging and up-regulation of antioxidant enzyme genes, decreased levels and antioxidation of LDL, increases in circulating HDL, inhibition of platelet activation and aggregation, and improvements in endothelial function. Berries have been shown to provide improvements in blood pressure or hypertensive status due to increased NO bioavailability via activation of endothelial NO synthase.
Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP <– we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. To demonstrate that dietary chlorophyll metabolites can modulate ATP levels, we examined the effects of the chlorophyll metabolite pyropheophorbide-a (P-a) on ATP synthesis in isolated mouse liver mitochondria in the presence of red light (lmax5670 nm), which chlorin-type molecules such as P-a strongly absorb (Aronoff, 1950), and to which biological tissues are relatively transparent. We used P-a because it is an early metabolite of chlorophyll, however, most known metabolites of chlorophyll can be synthesized from P-a by reactions that normally take place in animal cells The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight. We show that dietary metabolites of chlorophyll can enter the circulation, are present in tissues, and can be enriched in the mitochondria. When incubated with a light-capturing metabolite of chlorophyll, isolated mammalian mitochondria and animal-derived tissues, have higher concentrations of ATP when exposed to light, compared with animal tissues not mixed with the metabolite. The hypothesis is that photonic energy capture through dietary-derived metabolites may be an important means of energy regulation in animals.
To synthesize ATP, mitochondrial NADH reductase (complex I) and succinate reductase (complex II) extract electrons from NADH and succinate, respectively. These electrons are used to reduce mitochondrial CoQ10, resulting in ubiquinol (the reduced form of CoQ10). Ubiquinol shuttles the electrons to cytochrome c reductase (complex III), which uses the electrons to reduce cytochrome c, which shuttles the electrons to cytochrome c oxidase (complex IV), which ultimately donates the electrons to molecular oxygen. As a result of this electron flow, protons are pumped from the mitochondrial matrix into the inner membrane space, generating a trans-membrane potential used to drive the enzyme ATP-synthase.
Photons of red light from sunlight have been present deep inside almost every tissue in the body. Photosensitized electron transfer from excited chlorophyll-type molecules is widely hypothesized to be a primitive form of light-to-energy conversion that evolved into photosynthesis. Electrons would be transferred by a metabolite of chlorophyll to CoQ10, from a chemical oxidant present in the mitochondrial milieu. Many molecules, such as dienols, sulfhydryl compounds, ferrous compounds, NADH, NADPH and ascorbic acid, could all potentially act as electron donors. Intense red light between 600 and 700 nm has been reported to modulate biological processes. . Exposure to red light is thought to stimulate cellular energy metabolism and/or energy production by, as yet, poorly defined mechanisms. On a clear day the amount of light illuminating your brain would allow you to comfortably read a printed book. Photons between 630 and 800 nm can penetrate 25 cm through tissue and muscle of the calf . Adipose tissue is bathed in wavelengths of light that would excite chlorophyll metabolites. Utilization of these facts may have the potential for new therapies. A potential pathway for photonic energy capture is absorption by dietary-derived plant pigments. Dietary metabolites of chlorophyll can be distributed throughout the body where photon absorption may lead to an increase in ATP .
Polyphenols have been shown to exhibit neuroprotective effects suppress neuroinflammation and activate antioxidant mechanisms.
A polyphenol found in pomegranate fruit, punicalagin, inhibits neuroinflammation in LPS-activated rat primary microglia by suppressing the production of pro-inflammatory cytokines (TNF- and IL-6), and PGE2 after 24 h of stimulation with LPS.
Punicalagin, which is a polyphenol – a form of chemical compound found in pomegranate fruit, can inhibit inflammation in specialised brain cells known as microglia. This inflammation leads to the destruction of more and more brain cells, making the condition of Alzheimer’s sufferers progressively worse . Recent results suggest that punicalagin inhibits neuroinflammation in microglia through interference with NF-[kappa]B signalling.
It is recommended to consume juice products that are 100 per cent pomegranate, meaning that approximately 3.4 per cent will be punicalagin. Unfortunately, most of the anti-oxidant compounds are found in the outer skin of the pomegranate, not in the soft part of the fruit. Pomegranate may be useful in neuroinflammatory conditions other than Alzheimer’s disease, including cancer and Parkinson’s disease.
Bottom Line: EAT YOU pomegranates! Punicalagin is good for your brain. The juice is the best was to get the most of the phytonutrient. It’s role in reducing the risk of Alzheimer’s disease and other inflammatory conditions is still being evaluated, but seems very promising.
Below is Nonsense relating to neuroinflammation, studies involving Punicalagin, and cytokines in the CNS:
Cytokines are polypeptides (proteins) that cause inflammation, immune activation, cellular differentiation, and death. They include interferons (INF) , tumor necrosis factor (TNF) , interleukins(IL) , chemokines, and growth factors. None of these are present to any degree in healthy tissues, but rather are induced by cell damage and tissue injury.
In the CNS, Tumor necrosis factor alpha (TNFa), Interleukin-1 (IL-1), and Transforming Growth Factor Beta (TGFb) are primarily the main cytokines. Each of these cytokines binds a specific receptor, which activates a process or signaling pathway, which include the NfkB and MAPK (mitogen activated protein kinase) pathways.
In the CNS, other cytokines include:
Chemokines (fractalkine, IL-8, RANTES)
Neuropoietic cytokines (IL-6, IL-11)
In a very basic categorization, the pro-inflammatory cytokines are : IL-1, TNF-a, IL-6, and the anti-inflammatory cytokines are IL-1ra (IL-1 receptor antagonist), IL-10, and TGFb
It has been noted that TNFa and IL-1 increase in the brain prior to neuronal death, and there are increased cytokines in stroke. The presence of IL-6 and TNFa are found to be increased in areas of tissue injury and in tissues in which there were poor clinical outcomes.
Some cytokines are synergistic – i.e. IL1 and TNFa or INFg (gamma) cause neurotoxicity when they are around together. TNFa may have a dose-dependent neurotoxicity.
IL-1ra inhibits brain damage caused by injury or excitotoxins.
If you inhibit IL-1ra, it has been found that ischemic damage occurs more frequently, hence IL-1ra is protective in the brain. If you block it, then you lose protection.
TGFB2 receptor (which binds protective TGFB), will induce damage in the brain by removing the protective TGFB, but having too much TGFb causes autoimmune encephalitis. Thus too much of a good thing can cause problems as well!
SO again :
IL-1 = neurodegenerative
IL-10 = protective against injury
TNFa/IL-6 cause damage, but sometimes inhibit damage. It’s not always just they cytokines presence but WHEN they are present that counts. Il-1 and TNFa protect neurons if they are present BEFORE an injury, but if delivered at the time of injury, they cause destruction.
Different cells in the brain secrete cytokines. Glia, endothelial cells (lining of blood vessels), microglia, and neurons express TNFa, which in turn induces IL-10 that feeds back to decrease TNFa production (negative feedback). There is a TNF alpha binding protein that influences and decreases TNFa and also fractalkins that cause microglia to secrete less TNFa as well. All of these create feedbacks to limit cytokine production in complicated ways.
When damage occurs, the microglia (structural cells in the brain) first produce IL-1b(beta). The damage to cells causes extracelular ATP to be released and that activates P2X7 receptors that cause decreased intracellular potassium. This results in caspase 1 activation that causes the production of IL-1B, which in turn KILLS microglia and macrophages in the brain.
Also, during injury, TNFa release causes TGFb/IL6 expression.
Injury causes IL-1 to induce TNFa, IL-6, TGFb expression as well!
Infection and inflammation in the brain or periphery cause increased CNS cytokines and further inflammation. Hence peripheral inflammation affects CNS inflammation as well.
Excitotoxic amino acids also regulate cytokines after CNS injury as below:
Postsynaptic Density Protein 95 binds NMDA receptor subunit NR2 and Kainate recptor GLUR6 – which then phosphorylates C-JUn-N terminal kinase (JNK) and activates JUN. JUN promotes IL-1, IL-6, TNFa, INFa/g production.
Of note Cannabomids INHIBIT TNFa and IL-1 release from glial cells and are anti-inflammatory.
Neurons depend on glial cells for survival. Glial cells (astrocytes) produce neurotropins and growth factors (nerve growth factor (NGF), BDNF, GDNF)
Cytokines affect blood flow in the CNS as well indirectly. IL-1 induces neovasculariztion. IL-1 and TNFa damage the blood brain barrier and allow migration of molecules in and out of the CNS. They also cause NO (Nitric oxide) to be released, which is neurotoxic. They also upregulate adhesion molecules for leukocytes, that then enter the brain. What follows in vasogenic edema (swelling).
IL-1, IL-6, and TNFa also mediate fevers, endocrine reactions, and cardiovascular changes. This causes increased neuronal loss by alterations in blood flow and inflammation.
The COX-2 enzyme pathway and subsequent generation of prostaglandins play a significant role in neuroinflammation. mPGES-1 is the terminal enzyme for the biosynthesis of PGE2 (prostoglandin) during inflammation, and is functionally coupled with COX-2. This enzyme is markedly induced by pro-inflammatory stimuli and is down-regulated by antiinflammatory glucocorticoids – mPGES-1 inhibitors produced inhibition of PGE2 production
The transcription factor NF-B plays a crucial role in neuro-inflammation.
In resting cells, NF-B is sequestered in the cytoplasm by the inhibitory IB protein. When activated by a variety of stimuli that includes LPS (lipopolysacharride), IB is phosphorylated by IKK. Phosphorylated IB then undergoes ubiquitinisation and degradation . Dissociation and degradation of IB activates the translocation of NF-B subunit from the cytosol to the nucleus. The translocated subunit thereafter facilitates the transcription of several pro-inflammatory genes, including those encoding pro-inflammatory cytokines, and COX-2. Furthermore, microglial NF-B activation has been linked to brain damage
Punicalagin significantly inhibited LPS-induced NF-B signalling in microglia by suppressing the phosphorylation of IKK, IB and nuclear p65
Punicalagin produced a modest suppressive action on the phosphorylation of p38 and JNK MAPKs following LPS activation
Treatment with LPS in primary astrocytes triggered the synthesis of inflammatory cytokines, through MAPKs signalling pathways. Of particular interest is the role of p38, which has been shown to be a critical mediator of LPS-induced inflammation .
It appears that the effects of punicalagin on neuroinflammation are mediated mainly through targeting NF-B signalling, while MAPKmediated actions are minimal. Studies have shown that the TLR-4-mediated TRAF- 6/IKK/NF-B pathway has been well established as a signalling pathway responsible for inflammatory responses.
In addition to NF-B activation, TLR-4 can also initiate MAPK signalling
Punicalagin inhibited TRAF-6 protein expression, suggesting that this compound may inhibit the IKK/IB/NF-B signalling pathway, as well as p38 and JNK MAPK via selective inhibition of TRAF-6
Treatment with LPS in primary astrocytes triggered the synthesis of inflammatory cytokines, through MAPKs signalling pathways.
The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer <<– The p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion. The p38 MAPK, originally referred as cytokine-suppressive anti-inflammatory drug binding protein (CSBP). p38 MAPK is activated by pro-inflammatory cytokines such as interleukins and TNF-α. Stimulation of receptors that initiate this cascade include GPCR, cytokine receptors, Toll-like receptors, growth factor receptors, and receptors associated with environmental stress such as heat shock, radiation and ultraviolet light. p38 MAPK is activated by upstream MAPK kinases (MKK) p38 MAPK pathway plays a central role in the expression and activity of pro-inflammatory cytokines such as TNF-α, IL-1, IL-2, IL-6, IL-7, and IL-8 and plays a regulatory role in cell proliferation and differentiation in the immune system. It also regulates the expression of several MMPs involved in inflammation such as MMP-2, MMP-9, and MMP-13.
There is involvement of p38 MAPK in cancer cell invasion. Of note, p38α and p38β were found to play important roles in cell differentiation and invasion of several different cancer cells such as breast cancer, squamous carcinoma cell, colon cancer, and ovarian cancer
Common pathways of neuronal cell death have been identified in response to diverse insults, such as ischaemia, trauma or excitotoxicity. These include early disruption of ion homeostasis, excessive neuronal activation, seizures and spreading depression, massive release and impaired uptake of neurotransmitters such as glutamate, intracellular entry of Ca2+, and release of nitric oxide and free radicals. More recently, further factors have been identified, including activation of genes that initiate or execute apoptosis, and the influence of glial and endothelial cells, extracellular matrix and invading immune cells. There is evidence that specific cytokines can act at most, if not all, of these steps, and probably have multiple actions on several cells or systems involved in neurodegeneration.
Increased expression of p38 MAPK and extracellular-signal-regulated kinase (ERK) has been found in ischaemic brain tissue after MCAo. Selective inhibitors of these pathways markedly reduce the ischemic injury in rodents. TNFR1 and TNFR2 (Tumor necrosis factor receptors) belong to the low-affinity neurotrophin receptor gene superfamily. TNFα elicits its biological effects on multiple cell types in the CNS through these receptors.
TGFβ- mediated signalling is also regulated through crosstalk with other signal transduction pathways, including MAPK.
So, IL-1ra, or a small molecule antagonist of IL-1 receptors, might be beneficial in acute neurodegenerative conditions. Studies are currently evaluating this.
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HS is a chronic inflammatory skin disease associated with the formation of multiple abscesses, nodules, and scars in the apocrine gland-bearing areas. Sites that are affected include inguinofemoral (groin), axillary (arm pit) , perianal, gluteal (buttocks) , and submammary (breast) regions. Approximately 1-4% of the population is affected by this disorder. The apocrine (sweat) glands get occluded by hyperkeratotic (skin material) debris that produce follicles that rupture and cause inflammation.
The course of HS can vary from small pustules to inflammatory nodules, and in some cases become inflammatory, deep abscesses and draining sinus tracts. In other words, an infected pock marked mess.
This disease is staged in to three categories with Stage 1 being basic abscesses without scarring and Stage 3 being the worst, having destroyed completely an area with multiple abscesses that can be interconnected and have sinus tracts (holes) connected to the skin surface.
For those with this disorder, wearing loose fitting clothes that don’t rub the areas involved, not pinching the lesions, wearing antiperspirants but not applying perfumes to the area are helpful. Topical anti-bacterial cleansing with Triclosan-containing soaps will decrease bacterial colonization. Don’t scrub the area when washing as that will inflame the lesions more.
Primary treatment includes quitting smoking – which is highly associated with Hidradenitis Suppurativa. If you continue to smoke, don’t expect to get better. Also weight loss is important as 2/3 of those with HS are overweight. The HS may be due to elevated insulin levels, hormonal changes, and dietary problems in these individuals. Avoiding dairy and high glycemic loaded foods can decrease the disease.
Metformin, an anti-diabetic drug can be helpful in decreasing the HS disease burden. This is a result of the insulin-sensitizing effect of Metformin as it is believed that HS results, in part, from elevated insulin levels.
Treatment methods, after the basics listed above, include the use of Resorcinol, a chemical peeling agent, which as a 15% solution and applied twice a day, can improve the HS lesions and decrease pain and inflammation.
Also used are antibiotics, usually Doxycycline and minocycline first line, then Clindamycin if those are not helpful. Clindamycin mixed with Rifampin has been effective in 2/3 of patients with moderate disease. Some physicians use a combination of Moxifloxacin, Rifampin, and Metronidazole with good success.
Dapsone, an antibiotic with immunomodulatory effect, has had effect in early stage disease.
Intralesional injection of steroids is another option for local treatment as a monthly injection over a period of three months or so. Occasionally surgery must be done or an incision and drainage when a large abscess forms.
Androgens can promote the development of HS. It has been found that drospirenone- (or norgestimate-) containing oral contraceptives with spironolactone ( a blood pressure medication with anti-androgen effects) has been helpful in women.
For patients who don’t want to quit smoking or cannot lose weight and for those who fail other medical therapies, anti-TNF (tumor necrosis factor) agents are effective and have been approved for use in HS. The injected agent Infliximab was found to have a 50% reduction in severity score with most having improvement in pain and quality of life. Adalimumab was recently FDA approved for HS treatment but has been less effective. Whereas Infliximab is administered by weekly infusions, Adlimumab is given by subcutaneous weekly injections. The problems with the anti- TNF agents include risks for infection, heart failure, demyelinating disease, a lupus-like syndrome, and malignancy.
Oral retinoids such as acitretin and Isotretinoin have shown beneficial effect as well. Acitretin given as 0.6 mg/kg daily for 9 to 12 months showed highly effective in diminishing the disease, an effect that remained after the medicine was stopped, unlike with the biological agents, which have a higher relapse rate after discontinuance. Isotretinoin also has been effective in several studies with lower relapse after discontinuance. Both agents are highly teratogenic.
Systemic prednisone can decrease inflammation when given over 7-10 days at 40 mg a day. Cyclosporine has also been used as well.
Vitamin D3 supplementation at 300-6000 Units daily has been helpful in decreasing HS lesions in some individuals.
Zinc salts have antiinflammatory and antiandrogenic properties. Zinc Gluconate at 90 mg daily was very effective (36%) in significantly decreasing the inflammation of low grade HS, with beneficial effect in most who use zinc supplements.
What is interesting about Hidradenitis Suppurativa, is the inflammatory component of the disease. We know that the risk of the disease increases with obesity and cigarette smoking, which are also associated with elevated markers of inflammation themselves. Obesity is associated with elevated inflammatory markers and insulin levels, which appear to play a role in the genesis of HS as well as other diseases (i.e hypertension, fatty liver, diabetes, cancer, etc) In the article listed below, it was recognized that HS and the risk of it’s progression can be estimated by CRP levels, a marker of total body inflammation. CRP is produced by the liver in response to IL-6, another inflammatory marker. This generalized inflammation affects multiple organ systems.
The above study examined the use of CRP and white blood count (wbc) in estimating the risk of progression and inflammatory content of patients with various stages of HS.
The study found that CRP level and neutrophil counts are effective tools for assessing the extent of disease severity and grade of inflammation in patients with HS above and beyond the association of these inflammatory markers with coincidental comorbidities. For example, obese patient have elevations in CRP and smokers have higher white blood cell counts, but this study showed that CRP and wbc independently predicted worse disease status in patients with HS. There was a significant correlation between these inflammatory serum markers and disease severity according to HS severity grading scale. The end finding is that CRP is a significant and independent predictor for severe disease activity of Hidradenitis Suppurativa.
What interests me about this disease is it’s associations with comorbidities. Smokers have little hope of remission of HS and HS is associated strongly with obesity. These same disorders are inflammatory in their own right. It is felt that the elevated levels of insulin and insulin resistance in obesity may play a role in worsening of HS. Obesity and the hormonal catastrophe associated with it is also associated with coronary heart disease, hypertension, fatty liver, and a host of other life-limiting diseases. So again, here is a disease process (HS) that is, in part, partially a creature of our own design – bad habits. If we could stop smoking and limit obesity, how much HS would really exist?
More and more evidence is linking inflammation to depression. Inflammation is associated with many different illnesses including heart disease, diabetes, and now brain disorders such as depression, schizophrenia, and Alzheimer’s disease. People with chronic diseases that have high levels of inflammation associated with them are prone to depression. Evidence is stacking up that the inflammation is the cause of the depression.
Depressed patients tend to have higher levels of inflammatory markers that are associated with depression. You can inject people with inflammatory messengers and produce depression likewise. Think about the use of interferons in multiple sclerosis and the depression that it causes as a result of the inflammatory messengers produced.
In children exposed to adversity/stress, inflammatory markers such as CRP and Interleukin-6 increase and this was associated with increased levels of depression in the children. Of course not all became depressed, but the elevation of these inflammatory markers was associated with increased risk of depression over the next 6 months ( “Clustering of Depression and Inflammation in Adolescents Previously Exposed to Childhood Adversity” by Gregory E. Miller and Steve W. Cole (doi: 10.1016/j.biopsych.2012.02.034). Biological Psychiatry, Volume 72, Issue 1 (July 1, 2012))
The article listed above is an excellent summary of concepts in the role of inflammation in psychiatric disorders. Key concepts that are brought out include: We cannot indiscriminately use treatments for inflammation in psychiatric disorders unless inflammation exists in that particular patient. (2) Specific circuits in the brain are targets of inflammation such as the basal ganglia and cortical circuits (dorsal anterior cingulate, amygdala, and insula) which mediate anxiety, arousal and alarm. These pathways inhibit motivation and activate arousal to allow the body to shunt energy to fight infection and heal wounds while increasing vigilance against attack. This is a self-preservation measure. (3) Not all anti-inflammatory agents are equal. Some anti-inflammatories have off-target effects in which they modify a disorder indirectly. For example, minocycline, an antibiotic, is effective in some schizophrenia patients by inhibiting microglia activation , which is inflammatory. However, the minocycline also alters the gut biome, which also effects and mediates behavior. (4) The bottom line is that there will probably be need for direct anti-inflammatory agents, such as monoclonal antibodies that target TNF and IL-1 without affecting peripheral targets. (4) The only measure of actual inflammation are the peripheral markers that include CRP, IL-6, and TNF, which are elevated in inflammatory conditions. How they relate to central inflammatory markers is unknown.
The bacteria in your gut create a huge ecosystem or biome that has major effects on your overall health. More and more studies are demonstrating this, including the one below.
The gut microbiota diversity and function plays a role in the development of obesity and metabolic ailments.
Akkermansia muciniphila is a mucin-degrading bacteria found in the mucus layer of the intestine that has been found to help improve your metabolic status by increasing insulin sensitivity and glucose regulation.
Obese individuals and those with Type 2 diabetes differ from leaner individuals in the constitution of their gut micobiome and the microbial gene richness. It has been found in mice that higher levels of mucin-degrading bacteria (Akkermansia muciniphila) are inversely associated with body fat and glucose intolerance. In other words, these bacteria help improve glucose metabolism and improve overall metabolic health.
The article below demonstrated that Akkermansia muciniphila, when increased in the gut, resulted in healthier metabolic status in obese people. This was accomplished by caloric restriction, which then resulted in increased microbial gene richness ( a good thing) and improved glucose homeostasis and blood lipids. Following a FODMAP diet also increased Akkermansia muciniphila in the gut.
The higher the Akkermansia muciniphila bacteria levels are in the gut, it seems that you will have better glucose metabolism, better waist-to-hip ratios, lower fasting glucose levels, better triglyceride levels, and better fat distribution.
Increasing amounts of fat in the form of fat hypertrophy is a proinflammatory condition and is associated with bad cardiometabolic risk. This inflammatory risk is measured through insulin levels, interleukin-6, lipopolysaccharide levels, and C reactive protein levels in the blood stream. Caloric restriction leads to increased Akkermansia muciniphila and other healthy bacteria, which increases the overall microbial gene richness. These bacteria lower the inflammatory markers through their metabolic activity. This results in better metabolic outcomes.
How does this all occur? Akkermansia muciniphila ferments waste products into other items that other beneficial bacteria species can feed on. Short chained fatty acids are one of those items as well as acetate, which becomes an anorectant when absorbed in the body. In other words, you eat less.
The key here is that the gut biome plays a tremendous role in our overall health, and caloric restriction results in a boosting of the healthy richness of our gut biome, which is probably a key part of overall health!
Dao M, Everard A, et al. Akkermansia muciniphilaand improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut.2015.
Gut Bacteria and Food Allergies:
Gut bacteria also seem to play an integral role in other aspects of our health including food allergies. The presence of Clostridia in our gut appears to be protective against food allergies by causing the release of Interleukin-22 from gut cells, thereby decreasing permeability of the gut to allergens, which cause allergic reaction. Without gut permeability, the antigens cannot create an allergic immune response. Food allergies have been increasing in recent times due to modern dietary and hygienic practices, which disturb our natural gut biome.High fat diets, antibiotics, and formula feeding have all affected our gut bacteria, some of which protect us against food allergies. In a study, it was shown that germ-free mice and mice treated with antibiotics both reacted to peanuts, however, when clostridia was introduced, the reaction went away! This demonstrates how Clostridia decreases food allergies. The study, “Commensal bacteria protect against food allergen sensitization,” was the source of this information.
Arthritis affects millions of individuals, reducing quality of life. There are multiple facets that can be addressed regarding arthritis pain and what to do, but I will address several points:
Exercise added to the daily routine is the best way to help combat arthritis. Unused joint cause increased pain. What type of exercise? Flexibility Exercises, strength training, and aerobic exercises all help combat joint pain. They also help an individual lose weight as well, which increases mobility.
Range of motion exercises can help with stiffness and can improve mobility. Flexibility exercises allow one to do this. Tai chi and yoga are examples.
Preserve your muscle mass with strength training at least three times a week. This also allows one to lose weight and helps maintain mobility. Muscle training helps support the joint structure and function, such as the knees. This decreases joint stress.
Aerobic exercises also add a lot to overall health and diminish joint pain. Swimming is low impact. Walking is another option.
Options to help arthritis pain:
Heat application: Relaxes the muscles and increases blood flow to affected areas, helping provide nutrients and oxygen. This is useful in multiple areas such as knee, neck, and back pain.
Cold Applications: Cold packs can be used acutely after exercise to decrease inflammation, muscle spasms, and pain, especially in the first 72 hours, after which, use heat.
Emotional support: Remember that a large challenge to arthritis is the emotional impact. Cognitive behavioral therapy is an option to help one cope with the pain of arthritis. Remember to keep busy and keep moving. Meditation can help overcome the negative emotions that can actually increase your pain. Pain can increase your anxiety and depression. Insomnia can result from arthritis pain, so the emotional impact is huge as arthritis affects so many facets in one’s life.
Acupuncture: This may be an option in some individuals. Consider going online to find a certified acupuncture specialist near you.
Spinal Manipulation Therapy (SMT): Look at the entire body and evaluate the triggers that aggravate arthritis. SMT can reduce stiffness and help with joint movement. These changes in joint mobility have a local effect on the chemical factors that cause inflammation and pain. The joint may be the culprit in causing stiffness or the muscles surrounding the joint may be inflamed or spastic, resulting in lower mobility and pain.
Physical Therapy: Consult your physician for a PT referral., which can help you find ways to promote strength and flexibility.
Quit Smoking: Smoking lowers bone density.
Remember that muscles support your bones, and it is important to increase your muscle mass as it provides numerous benefits in addition to supporting your joints and your back. The back, in particular, with it’s discs and small facets, is affected over time by pressure, which can be unloaded by stretching and strengthening the spinal muscles through basic exercises like:
Pelvic tilt exercises:
One -legged wind releasing
You need core muscle strength and flexibility to help preserve your back. The hip muscles need to have flexibility maintained as well for better back health. Consider doing this through the 4.hammerstring stretch:
Inflammation in the body breaks it down over time. Inflammation results from and, in part, causes autoimmune disorders and atherosclerosis with subsequent coronary artery disease and stroke. There are many ways to measure levels of inflammation in the body, but none are sensitive or specific for any particular condition. Likewise, inflammatory markers don’t always point to a specific treatment, but rather the presence of a system that is in trouble and needs thorough evaluation.
Inflammatory risk can be determined, in part, by elevations in C-reactive protein (CRP) and fibrinogen, which are both made in the liver as a result of the influence of cytokines such as interleukin-Ib, Interleukin-6 (IL-6), and Tumor necrosis Factor- alpha (TNF). Fibrinogen increases can increase your risk of platelet aggregation (clots) which increase stroke and heart attack risk.
There is evidence that DHEA and fish oil can decrease cytokine levels and decrease inflammation. Vitamin K can suppress IL-6 especially and thus decrease inflammatory markers. Nettle leaf extract has been found to suppress TNF-alpha and IL-1b cytokines. Aspirin, green tea, ginko bilboa, garlic, and Vitamin E have been found to decrease platelet aggregation and help blood flow, helping to avoid strokes and heart attacks. Lower fibrinogen levels may decrease the risk of myocardial infarction. Increased vitamin A levels decrease fibrinogen levels. Olive oil and fish have had a similar effect. Niacin (1000 mg a day) and vitamin C (2000 mg a day) will decrease fibrinogen. Bromelain (2000 mg/day) and EPA/DHA from fish oil also have a beneficial impact as well.
Elevated homocysteine levels also represent a cardiovascular threat. Elevated homocysteine prevents fibrinogen breakdown by inhibiting tissue plasminogen activator. Ways to diminish homocysteine levels and it’s risk include vitamin B12, vitamin B6, and trimethylglycine (TMG).
So elevations of homocysteine will increase your heart attack and stroke risk. Trimethylglycing (TMG) methylates homocysteine and converts it to methionine and s-adenosylmethionine (SAMe). In this process, the body needs folate and vitamin B-12. Homocysteine can also be removed from the body by the transsulfuration pathway using a vitamin B-6 dependent cystathione synthase enzyme. Vitamin B6 is necessary for this, and in some individuals, they lack the ability to produce the active form of vitamin B-6 (pyridoxal-5-phosphate), in which case, pyridoxal-5-phosphate can be supplemented instead to lower homocysteine.
So vitamins and supplements that decrease homocysteine to help preserve cardiovascular health include: TMG (500 mg a day), folate (800 mcg a day), vitamin B12 (200 mcg a day), inositol (250 mg a day), zinc (30 mg a day), and vitamin B6 (100 mg a day).
C-reactive protein: an inflammatory risk marker that increases under the influence of cytokines IL-6, IL-1B, and TNF-alpha. When elevated, heart attack risk increases by over two-fold .Studies have found that the statin rosuvastatin (Crestor) can decrease CRP levels and the inflammatory risk of heart attacks. Also helpful are aspirin, vitamin E, nettle leaf extract, DHEA, and fish oil.
So here is a basic list of inflammatory markers and cardiovascular risk markers that should be followed:
Cholesterol (HDL and LDL and triglycerides)
Obesity is a risk marker for heart attacks and cancer. Why is this? Increased circulating insulin and insulin resistance causes increased fat conversion of glucose and increased fat deposition. The increased insulin causes certain cancer types to grow as well as it serves as a growth factor.
The keys to successful strategies for health besides weight loss, include:
Blood pressure control
Decreased LDL cholesterol
Increasing your healthy HDL cholesterol
Decreasing inflammatory markers such as fibrinogen, CRP, homocysteine, and cytokines.
Exercise is important. Be certain to consult your doctor before starting any exercise regimen. Use and exercise every muscle, every day. Exercise increases blood flow and lymph drainage increases. It also builds strength and flexibility, as well as balance and decreased falling risk. You feel less depressed and have more energy.
Coenzyme Q10: (Ubiquinone) is beneficial for heart and brain functioning, as well as being a blood pressure lowering supplement. Cells need it for energy production in the mitochondria and deficiency is found in aging and a variety of degenerative disorders. Muscles and the brain have high numbers of mitochondria which need this supplement. Taken orally, CoQ10 is absorbed and incorporated into the mitochondria. As one ages, the body produces only half of what it should of this vital supplement. Dosing is 30-300 mg a day. Of note, statins (anti-cholesterol agent) destroy co Q 10, so it is very helpful to take co Q10 supplements while on any statin. There are studies demonstrating increased energy production in the brain and muscles with Co Q10 supplementation, and it has been noted that there is an antioxidant protective ability as well provided by coQ10. In fact, there is speculation that Parkinson’s disease may result, in part, by reductions of co Q 10 levels in the brain (35% less than normal controls) and that with supplementation, some patients with Parkinson’s disease have had diminished progression of the disorder. As we age, Parkinson’s disease becomes more common, and it may be due to mitochondrial dysfunction and oxygen free radical production due to co-Q10 deficiency which results in the loss of neurons, thereby producing Parkinson’s disease. There is suggestion that dosages of coQ10 up to 1200 mg a day (which has minimal side-effects) seems to diminish the progression of Parkinson’s disease in some patients. This may be a result of the preservation of mitochondrial function.
The average American diet has 37% fat content. The recommended amount is 25-35% according to the 2010 dietary guidelines. Four studies have shown the bad impact that high fat consumption during pregnancy has on the fetus.
Other studies demonstrated that a high fat diet in the pregnant mother causes the down-regulation of oxytocin systems in the brain of offspring and causes anxiety to be prevalant in the progeny. This effect does not occur in the pups of normal fed pregnant female rats. In this study it was found that the fewer numbers of oxytocin-positive neurons within the PVN (paraventricular nucleus), the more anxious the rats were as adults. Oxytocin projections to the brainstem acts as an appetite suppressant, hence leading to overeating in the progeny of overfed pregnant females. Oxytocin also plays a role in maternal behaviors as well. Mother rats literally groom their daughters to be attentive or neglectful mothers themselves and this is associated with the presence of normal numbers of oxytocin projections. If a rat has fewer oxytocin projections, they will be neglectful parents more likely. Hence multiple pathways of brain function may be affected in the young of a high-fat diet mother. Here is a link: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=93a801db-9e49-4d58-b917-97948ec69a18&cKey=74611e5c-0fa7-4ff0-9276-b94be31da2df&mKey=54c85d94-6d69-4b09-afaa-502c0e680ca7
These effects also occur in primate studies as well – monkeys whose mothers are fed high fat diets have fewer dopamine projections to the nucleus accumbens ‘reward center’ of the brain. As a result, they have a reward deficiency when they eat food and don’t get satiated at a normal level of food. Rather, they must take in more food to get the same amount of reward as another monkey that came from a normal-fed mother and had normal dopamine projections in the brain. Thus they get fatter.
We eat more than we think. We need to recognize that our food choices and stress patterns can affect our children through epigenetic mechanisms especially. We can set up our children for failure. These studies are done in standard models for humans and show the impact high fat diets in pregnancy have on their children: Memory deficits, anxiety, depression, and future weight problems may echo the studies in rat and monkey populations. The apple doesn’t fall far from the tree, for it seems that overweight parents have overweight children. Food for thought!!
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