The Mediterranean diet is a healthy diet that is not necessarily low-fat. It is low in omega-6 fatty acids and high in omega-3 fatty acids (olive oil). The use of herbs and spices in place of salt for seasoning makes the food more flavorful. Combined with 9 servings of fruits and vegetables every day, one gets plenty of nutrients from the diet. Red meat is eaten maybe twice a week as is fish, such as mackerel, herring, sardines, and anchovies. Eggs and poultry are eaten frequently but less than in an American diet. Wine or alcohol is common consumed with food. Mealtimes occur in a social setting with family and friends, which creates an excellent atmosphere. The diet is associated with lower rates of type 2 diabetes, Alzheimer’s disease, and cardiovascular disease.
A recent Review in The American Journal of Medicine (April 2016) as above evaluated MEDLINE, EMBASE, and the Cochrane libraries for randomized controlled studies of trials showing the effects of a Mediterranean diet with more than 12 months follow-up. Five RCT’s (998=n) were found and evaluated and compared the Mediterranean diet to a low-fat diet, a low carbohydrate diet, and an American Diabetes Association diet.
The Mediterranean diet resulted in a greater weight loss (4 to 10 Kg) when compared to a low-fat diet (3 to 5 kg loss), but produced similar weight loss at 12 months compared with the other diets.
The Mediterranean diet was found to be similar to the other diets in terms of cardiovascular risk factor levels, including blood pressure and lipid levels as well.
The Mediterranean diet has been found to work better than a low-fat diet based on this analysis. It also produced greater improvements in triglyceride levels but similar changes in other lipids and blood pressure. Likewise, the Mediterranean diet was better at improving glycemic (blood-sugar) control in diabetics ( but not non-diabetics).
There is no ideal diet for achieving sustained weight loss in overweight or obese individuals.
Long-Term Effects of 4 Popular Diets on Weight Loss and Cardiovascular Risk Factors << This study reviewed the Atkins, Weight Watchers, and the Zone, and demonstrated that all produced similar weight loss at 12 months and beyond. There is no demonstrable problem with the carbohydrate load in a Mediterranean diet, and the similar weight loss among these diets suggests no optimal macronutrient composition to sustain weight loss.
Weight loss is increased with the addition of exercise – physical activity and dieting added together give greater increments of weight loss than dieting alone. The references below include links to evidence for this:
Bottom line is that physical activity alone is unlikely to yield significant weight loss unless it is added to a calorie-restricted diet.
After these two components of exercise and low-calorie dieting, one then adds pharmacochotherapies. The final component is bariatric surgery for those who do not achieve goals and are of sufficiently high BMI and comorbidities.
The abstract of this study is below in which smoking and coffee intake both currently decrease the risk of PD:
A reduced risk for Parkinson’s disease (PD) among cigarette smokers has been observed consistently during the past 30 years. Recent evidence suggests that caffeine may also be protective. Findings are presented regarding associations of PD with smoking, caffeine intake, and alcohol consumption from a case-control study conducted in western Washington State in 1992–2000. Incident PD cases (n = 210) and controls (n = 347), frequency matched on gender and age were identified from enrollees of the Group Health Cooperative health maintenance organization. Exposure data were obtained by in-person questionnaires. Ever having smoked cigarettes was associated with a reduced risk of PD (odds ratio (OR) = 0.5, 95% confidence interval (CI): 0.4, 0.8). A stronger relation was found among current smokers (OR = 0.3, 95% CI: 0.1, 0.7) than among ex-smokers (OR = 0.6, 95% CI: 0.4, 0.9), and there was an inverse gradient with pack-years smoked (trend p < 0.001). No associations were detected for coffee consumption or total caffeine intake or for alcohol consumption. However, reduced risks were observed for consumption of 2 cups/day or more of tea (OR = 0.4, 95% CI: 0.2, 0.9) and two or more cola drinks/day (OR = 0.6, 95% CI: 0.3, 1.4). The associations for tea and cola drinks were not confounded by smoking or coffee consumption. Am J Epidemiol 2002;155:732–8.
But cigarette smoking is bad for your lungs, increasing cancer risks and emphysema among other things, so why would anyone want to smoke just to decrease PD risk? Is there another way to decrease PD risk and why do cigarettes work for PD?
The study at the top of the page (ANN NEUROL 2013;74:472–477) helps demonstrate the possibility that nicotine is neuro-protective among all the millions of compounds found in cigarette smoke.
Nicotine is derived from nicotiana spp. of solanaceae species which includes capsicum and solanum species whose edible fruits and tubers include peppers, eggplants, potatoes, and tomatoes. All of these have nicotine in them. In peppers, there is approximately 102 micrograms/kg, while tomatoes have 43 mcg/kg of nicotine. A potato has ~19 mcg/kg of nicotine. Since we consume more tomatoes and potatoes than peppers, they make up most of the nicotine consumption in people.
It is noted that nicotine stimulates alpha4beta2 (a4B2) receptors in the brain which protect dopaminergic neurons by binding the receptors. This may be how PD is prevented.
In the study, 490 people with PD were assessed for vegetable intake, in particular peppers, tomatoes, and potatoes. It was found that PD frequency was inversely related to solanaceae intake but not other vegetables, in particular peppers. Weighted for those with the most nicotine intake, those with the highest nicotine consumption had the lowest frequency of PD. There were 644 controls in this study.
After calculating risks, pepper consumption 2-4 times a week was associated with a 30% reduction in PD risk in people who did not smoke.
The food impact was highest in non-smokers since the nicotine content in food is so much lower than the intake of nicotine in active smokers.
There was an inverse association of PD in consumption of tomatoes (Fall PA, Fredrikson M, Axelson O, et al. Nutritional and occupational factors influencing the risk of Parkinson’s disease: a casecontrol study in southeastern Sweden. Mov Disord 1999;14:28–37) , potatoes ( Hellenbrand W, Seidler A, Boeing H, et al. Diet and Parkinson’s disease. I: A possible role for the past intake of specific foods and food groups. Results from a self-administered food-frequency questionnaire in a case-control study. (Neurology 1996;47: 636–643) and a Mediterranean Diet with tomatoes ( The Association between Mediterranean Diet Adherence and Parkinson’s Disease ) [ Abstract: The most consistent data support the association between higher consumption of dairy products and increased PD risk. More recently, a prospective analysis of two large cohorts, the Health Professionals Follow-Up Study (HPFS) and the Nurses’ Health Study (NHS), revealed an association between PD risk and dietary patterns as assessed by the Alternate Healthy Eating Index (AHEI) and the alternate Mediterranean Diet Score. The Mediterranean diet (MeDi) has received attention in recent years because of growing evidence associating MeDi with lower risk for AD, cardiovascular disease, several forms of cancer, and overall mortality.The MeDi is characterized by high intake of vegetables, legumes, fruits, and cereals; high intake of unsaturated fatty acids (mostly in the form of olive oil) compared to saturated fatty acids; a moderately high intake of fish; a low to-moderate intake of dairy products, meat and poultry; and a regular but moderate consumption of ethanol, primarily in the form of wine andgenerally during meals. This study suggests that lower adherence to MeDi is associated with PD status. The association persisted after adjustment for multiple potential confounders. The fact that among PD participants, lower adherence was associated with earlier PD age-at-onset further suggests a possible dose-response effect. The relation between MeDi adherence and PD status was not driven by any individual category of the diet but rather the whole pattern. Previous studies have indicated that environmental factors play a major role in PD; however, most nutritional studies in PD have shown conflicting results. Possible explanation for the conflicting data is that most studies have focused on single nutrients, e.g. vitamins C or E,7, rather than on dietary patterns. Indeed, the largest prospective study of dietary patterns identified a Mediterranean-like diet as protective of PD both in males (HPFS) and females (NHS). Assessing dietary patterns may be more informative than assessing specific nutrients separately. First, this approach is more consistent with individuals’ eating habits, and second, it takes into account interactions among nutrients. This approach has been successful in AD and in non-neurological diseases.The mechanism by which MeDi may be protective in neurodegenerative disorders is largely unknown. Mechanisms that have been hypothesized in the AD literature, include oxidative stress and inflammation. Indeed, oxidative stress has been implicated in the pathogenesis of PD. Complex phenols and other substances including vitamin C, vitamin E, and carotenoid may serve as antioxidants, and are found in high concentrations in the typical components of the MeDi. Inflammation has also been implicated in the pathogenesis of PD, and anti-inflammatory non-steroidal medications may be associated with a lower risk for PD. Adherence to the MeDi may attenuate inflammation. In addition, MeDi adherence may beprotective because of lower consumption of compounds which are associated with higher PD risk. We and others have shown an association between animal fat consumption and PD, and the association between higher dairy intake and PD was previously reported.]
There are still unknowns in this study – i.e relative to smoking, diet is a modest contributor of nicotine. Biological effects of Solanaceae nicotine has not been established but substantial a4B2 nicotine receptors are occupied without active smoking in patients who take in solanaceae products.As compared to smoking, smokers with just a puff get enough nicotine to occupy a third of the receptors for more than three hours. It is also unknown if french fries, salsa, sauces, or fried potatoes give a similar nicotine effect as the original vegetable.
There may be other neuroprotective chemicals in these vegetables such as Anatabine, which is antiinflammatory and has less toxicity. Anatabine Ameliorates Experimental Autoimmune thyroiditis << Key components: Tobacco smoking has numerous detrimental effects on human health, but it has also beenassociated with a few apparent salutary actions, including the amelioration of autoimmune (Hashimoto) thyroiditis and ulcerative colitis. Smokers in the Third National Health and Nutrition Examination Survey were found to have lower prevalence of thyroperoxidase and/or thyroglobulin antibodies than nonsmokers (1). This protective effect of smoking was confirmed in two additional cross-sectional studies, one from the Amsterdam autoimmune thyroid disease cohort (2) and the other from the Danish population (3), as well as in a 5-yr prospective study also based on the Amsterdam autoimmune thyroid disease cohort (4). In the prospective study, cigarette smoking women who had one or more relative with documented thyroid autoimmunity but no thyroid dysfunction or autoantibodies at study entry showed lower odds of developing thyroperoxidase and/or thyroglobulin antibodies (4). Similarly in ulcerative colitis, smoking has been shown to decrease flares (5), hospitalizations (6), and a need for oral glucocorticoids (7) so that low-dose smoking resumption has been successfully used in ex-smokers with refractory disease (8). The mechanisms underlying this influence of tobacco smoking on some autoimmune diseases have been related to the effects of tobacco components on the immune system (9). There are numerous (4000) components in tobacco, including alkaloids (such as nicotine and anatabine), gases (e.g. carbon monoxide), and carcinogens (e.g. polycyclic aromatic hydrocarbons, aldehydes, free radicals, and solvents), and of them nicotine is known to possess antiinflammatory properties (10). Nicotine acts via binding to the nicotinicreceptor, a pentameric ion channel (mainly for sodium and calcium) formed by the arrangement of 16 different subunits in hetero- or homomeric conformations (11). The receptor is classically expressed in the peripheral (all preganglionic fibers and neuromuscular synapses) and central nervous system, but more recently it has been described in cells of the immune system, including CD4 T lymphocytes, dendritic cells, and macrophages (12). Indeed, the 7-homopentameric nicotinic receptor has emerged as a novel therapeutic target for diseases with an inflammatory pathogenesis (13). Nicotine has been used successfully in mice with experimental autoimmune encephalomyelitis in which it reduced disease severity, shifting the autoimmune profile from pathogenic Th1 and Th17 responses to protective Th2 responses (14). Nicotine, however, cannot be used in humans because it is addictive and toxic and has a short 3-h plasma half-life. Consequently, we reasoned that other alkaloids of tobacco could share similar antiinflammatory properties but have a more favorable pharmacological profile. The minor tobacco alkaloid anatabine is nonaddictive and nontoxic at therapeutic doses and has a longer 8-hr half-life. Furthermore, anatabine has been recently shown to inhibit nuclear factor-B (NF-B) activation and reduce neuroinflammation in a mouse model of Alzheimer disease (15). In the present study, we therefore tested the antiinflammatory properties of anatabine in a mouse model of experimental autoimmune thyroiditis. Anatabine is an alkaloid with a structure similar to nicotine, found in tobacco and other solanaceous plantsas tomatoes, potatoes, green pepper, and eggplant. Its lack of addictive potential or any demonstrated toxicity. Given the structure similarity with nicotine, we postulated that anatabine initiates its effects by binding to the nicotine receptor and modulating the cholinergic control of inflammation (10, 24). The nicotinic receptor that has been clearly associated with antiinflammatory responses is the 7-homopentamer, classically found on neural cells but also on immune cells (12). Activation of the 7-nicotinic receptor present in lymphocytes, dendritic cells, and macrophages has been shown to suppress nuclear translocation of NF-B and transcription of high mobility group box 1, ultimately decreasing danger signals that initiate inflammation (25). Consistent with this mechanism, Paris and colleagues demonstrated that anatabine suppresses in a dose-dependent manner the transcription of NF-B induced by tumor necrosis factor- (15). However, anatabine suppressed the thyroidal expression of IL-18 and IL-1R2. IL-18, a member of the IL-1 family, is produced by activated macrophages and stimulates production of interferon- from T cells and natural killer cells (26), overall acting as a proinflammatory stimulus. IL-18 has been shown to increase during thyroid inflammation both in vitro (27) and in vivo (28) ]
Summary: To safely decrease your risk of Parkinson’s disease, increase your peppers, tomatoes, potatoes, and eggplant intake. They have nicotine that when consumed, is protective of dopaminergic receptors of your brain and seem to decrease the risk of PD.
A recent study released in the April 10 edition of The New England Journal of Medicine demonstrated that fresh fruit consumption was associated with decreased blood pressure and decreased blood glucose.
Increased fresh fruit consumption was associated with decreased risk of cardiovascular disease, decreased cardiovascular death, decreased coronary events, decreased hemorrhagic stroke, and decreased ischemic strokes.
The NEJM study released in this issue death with Chinese populations, some 450,000 Chinese in fact, with no prior stroke or hypertension to avoid confounding factors. IN Western populations, an inverse association had been seen in patients eating 80 gm of fruit a day, leading to a 5% decrease in cardiovascular death.
A low level of fruit intake is associated with a major increased cardiovascular risk rate. The study above chose China, since vegetable intake is high but fresh-fruit intake is much lower. Cardiovascular disease causes 17 million deaths a year and is especially high in lower income countries. The effect of adding fruit to the diet of people with low consumption rate can detect larger effects.
The association between the level of fruit consumption and cardiovascular risk in our study (a 40% lower risk of cardiovascular death and a 34% lower risk of major coronary events among participants who consumed fresh fruit daily as compared with those who never or rarely consumed fresh fruit) was much stronger than the associations observed in previous studies. < Current NEJM study April 2016. This study involved some 512,000 people who had low intake of fruit already, making it easy to detect positive benefits. None of the patients had hypertension or Diabetes, and thus were not on any confounding medications. The study also took into account regression dilution bias (changes in baseline characteristics of a population during a study) that may impact findings.
Fruit is high in fiber, potassium, folate, phytochemicals, and antioxidants all of which may mediate the positive impact of fruit intake.
In conclusion, our evaluation of the relationship between fresh fruit consumption and cardiovascular disease in China showed that the level of fruit consumption was inversely associated with blood pressure and blood glucose levels.
Humans have always been in contact with the earth’s electrical field since the beginning of time. That has changed with the advent of shoes, which have separated us from a direct connection with the earth. The earth is full of electrons that freely travel to things in contact with it. The build up of electrical charges in our bodies as our systems function in their usual way is impacted by direct grounding connection to the earth, which can restore neutrality of our body’s electrical potential. Mounting evidence suggests that the Earth’s negative potential can create a stable internal bioelectrical environment for the normal functioning of all body systems. Moreover, oscillations of the intensity of the Earth’s potential may be important for setting the biological clocks regulating diurnal body rhythms, such as cortisol secretion.
There is evidence that electrons from antioxidant molecules neutralize reactive oxygen species (ROS- free radicals) involved in the body’s immune and inflammatory responses. Electrons are absorbed into the body through direct contact with the Earth and likely neutralize ROS and reduces acute and chronic inflammation. Because the body is electrically conductive, free electrons are able to enter the body.
During recent decades, chronic illness, immune disorders, and inflammatory diseases have increased dramatically, and some researchers have cited environmental factors as the cause. However, the possibility of modern disconnection with the Earth’s surface as a cause has not been considered.
Earthing (also known as grounding) refers to contact with the Earth’s surface electrons by walking barefoot outside or sitting, working, or sleeping indoors connected to conductive systems, some of them patented, that transfer the energy from the ground into the body. The Earth’s electrons induce multiple physiological changes of clinical significance, including reduced pain, better sleep, a shift from sympathetic to parasympathetic tone in the autonomic nervous system (ANS), and a blood-thinning effect.
Patients who practice grounding reportsignificant relief from asthmatic and respiratory conditions, rheumatoid arthritis, PMS, sleep apnea, and hypertension while sleeping grounded.
The majority of subjects with high- to out-of-range nighttime secretion levels of cortisol experienced improvements by sleeping grounded. This is demonstrated by the restoration of normal day-night cortisol secretion profiles in individuals that sleep while grounded. Patients sleep more and fall asleep quicker by being grounded, with less daytime fatigue and sleepiness and less nighttime pain.
One study showed that when the body is grounded, its electrical potential becomes equalized with the Earth’s electrical potential through a transfer of electrons from the Earth to the body. Feynman said that when the body potential is the same as the Earth’s electric potential (and thus grounded), it becomes an extension of the Earth’s gigantic electric system. The body of the grounded person is not subject to the perturbation of electrons and electrical systems. There is no question that the body reacts to the presence of environmental electric fields, which induce changes in our own bodies and grounding, just like a house’s electrical system, is equilibrated by this process.
Earthing the human body showed significant effects on electrophysiological properties of the brain and musculature, and on the noise and stability of electrophysiological recordings. Taken together, the changes in EEG, EMG, and BVP suggest reductions in overall stress levels and tensions and a shift in ANS (Autonomic nervous system) balance upon earthing. An immediate decrease (within a few seconds) in skin conductance (SC) at grounding and an immediate increase at ungrounding blood oxygenation (BO) variance decreased during grounding The immediate decrease in SC indicates a rapid activation of the parasympathetic nervous system and corresponding deactivation of the sympathetic nervous system. This is good for human health. Pain reduction from sleeping grounded has also been documented.
Muscle injury in humans causes inflammation, and studies of grounding demonstrate more rapid recovery. Grounded men had only a slight decrease in white blood cells, indicating scant inflammation and a shorter recovery time in muscle injury.
Grounding may also improve heart rate variability (HRV), a measurement of the heart’s response to ANS regulation. During the grounded sessions, participants had statistically significant improvements in HRV.
Grounding during a single night of sleep resulted in statistically significant changes in concentrations of minerals and electrolytes in the blood serum: iron, ionized calcium, inorganic phosphorus, sodium, potassium, and magnesium. Renal excretion of both calcium and phosphorus was reduced significantly. This may impact bone loss.
Earthing accelerated the immune response, as demonstrated by increases in gamma globulin concentration.
In the absence of Earth contact, internal charge distribution will not be uniform, but instead will be subject to a variety of electrical perturbations in the environment. Absence of a common reference point, or “ground,” electrical gradients, due to uneven charge distribution, can build up along tissue surfaces and cell membranes. Charge differentials will influence biochemical and physiological processes Local alterations in the charge profiles around these channels can lead to electrical instability of the cell membrane and to the inappropriate spontaneous activity observed during certain pathological states (i.e pain and inflammation)
Reduction in inflammation as a result of earthing has been documented with infrared medical imaging and with measurements of blood chemistry and white blood cell counts. The logical explanation for the antiinflammatory effects is that grounding the body allows negatively charged antioxidant electrons from the Earth to enter the body and neutralize positively charged free radicals at sites of inflammation.
Earthing also significantly reduces blood viscosity.
Rapid shifts in the ANS from sympathetic to parasympathetic dominance, improvement in heart rate variability, and normalization of muscle tension has been seen in studies of people who were grounded.
Going barefoot as little as 30 or 40 minutes daily can significantly reduce pain and stress in some studies.
So the bottom line is there a benefit to barefoot walking in nature. The earth, with it’s negative ionic charges, conducts into our bodies in a positive manner. Walking, sitting, laying all allow electrons to flow into the body and there is a belief that his promotes health. Earthing improves blood viscosity, heart rate variability, inflammation, cortisol dynamics, autonomic nervous system functioning, and decreases stress levels.
Standing in sand at the beach, for example, drains the positive ions causing stress and inflammation. The body-spirit complex is helped in the process, allowing us to feel renewed.
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 .
PCSK9 (proprotein convertase subtilisin kexin type 9) binding to LDL receptors on hepatocytes promotes receptor degradation, prevents LDL-C clearance from blood, and increases serum concentrations of LDL-C. Evolocumab and Alirocumab are human IgG2 monoclonal antibodies that targets PCSK9, prevents it from binding to LDL receptors, and increases hepatic uptake of LDL-C.
The second FDA-approved PCSK9 inhibitor evolocumab (Repatha) appears to be similar in efficacy and safety to alirocumab (Praluent), but no comparative studies are available
Concerns are arising that the use of PCSK9 inhibitors are related to cognitive adverse events (CAE). These events include delirium, cognition and attention disorders, dementia, disturbed thinking and perceptive disorders, and memory impairment.
Two trials brought this concern to light: The OSLER study (Evolocumab) and the ODYSSEY LONG TERM study ( Alirocumab). Both trials demonstrates an increased incidence of neurocognitive deficits, but these evnts were SELF-REPORTED events, for which there was no formal neuropsychiatric testing.
In the OSLER study for Evolocumab, there were 1104 patients evaluated using Evolocumab (420mg) and standard of care treatment versus standard of care treatment alone, Of all these patients, three reported amnesia and 5 reported memory impairment, whereas none did so in the standard of care group.
The treatment patients had visits every 4 weeks versus standard of care (not treated with Evocolumab) who visited every 12 weeks with physicians, thus creating a potential responder bias by self reporting. Because the treated group was seen three time more frequently, there could be ascertainment bias involved since they had more opportunity to complain.
An 11 month follow up showed CAE’s in Evolocumab to be 0.9% versus 0.3% of those in the non-PCSK-9 treated group. There was no association between degree of LDL lowering and the self-reported cognition issues.
In the ODYSSEY LONG TERM trial, Alirocumab use was evaluated. The CAE events were 1.2% versus 0.5% in the placebo group similar to the OSLER trial.
Again the cognitive effects were all SELF-REPORTED n the above trials.
An investigation looking at cognitive issues with PCSK-9 inhibitors is being initiated currently: Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects (EBBINGHAUS) (ClinicalTrials.gov Identifier: NCT02207634). Participants without dementia or mild cognitive impairment at baseline will be randomized in a double-blind, placebo-controlled, multicenter study to evaluate evolocumab + background statin therapy versus statin therapy alone. The primary outcome will be the Spatial Working Memory test, an assessment of executive function. Results are expected in September 2017 with an enrollment of 4,000 subjects. ( Early Evidence Linking PCSK9 Inhibitors to Neurocognitive Adverse Events: Does Correlation Imply Causation )
You may recall that statins have also faced years of controversy regarding cognitive effects, none of which have panned out. The fact remains that in the OSLER and ODYSSETY trials, there is a 50% reduction in cardiovascular events that offers benefits to a huge group of patients in spite of the neurocognitive risk, much of which is undefined. Remember: correlation does not equal causation and subjectively-reported adverse events are potentially fraught with bias. Even coronary heart disease has been associated with impaired cognition.
records of 1,921 adults between the ages of 40 and 79, each of whom participated in the National Health and Nutrition Examination Surveys (NHANES) during the years 2009 and 2010
In the study, the 1921 participants had FEV1 and FVC measured along with the percent FEV1 and FVC to look at airflow restirciton and obstruciton and apllying GOLD and Spirometry Grade classifications to determine airflow issues. Patients were categorized by grams of fiber consumed to asses change in airway parameters. Subjects in the highest quartile intake of fiber had mean FEV1 and FVC measurements that were 82 mL and 129 mL higher that the lowest quartile of intake (p=0.05 and 0.01, respectively), and mean percent predicted FEV1 and FVC values that were 2.4 and 2.8 percentage points higher (p=0.07 and 0.02, respectively)
Higher fiber intake was associated with a higher percentage of those with normal lung function (p=0.001) and resulted in a significant decline in the proportion of participants with airflow restriction (p=0.001)
Participants consuming more than 17.5 grams of fiber daily comprised the top quartile (and, at 571, the largest number of participants), while those whose diets included less than 10.75 grams each day (360 participants) were in the lower and smallest group
Bottom Line: 17 grams of fiber per day from fruits, vegetables, and legumes had better lung health, compared with those who consumed the least. Fiber decreases inflammation!
As gut microbes are starved of fermentable fiber, some do die off. Others, however, are able to switch to another food source in the gut: the mucus lining. As fiber consumption increased, the activity of genes associated with protein metabolism declined. that this fuel switch had striking consequences in rodents. A group of mice fed a high-fiber diet had healthy gut lining, but for mice on a fiber-free diet, “the mucus layer becomes dramatically diminished
Notes: Yogurt, which is fermented milk, the main bacteria are Streptococcus thermophilus and lactobacillus.
Yogurt bacteria generally last two weeks in our gut. They help break down complex polysacharrides (sugars):
Xylans: polysaccharides in fruits, vegetables, milk, wheat
Pectins: found in apples, plums, orange, carrots – pectins are the jelling agents in jams and jellies
Fructans: found in barley, wheat, garlic, onion, and asparagus
Dietary-fat-induced taurocholic acid promotes pathohbiont expansion and colitis <<–Summary : we show that consumption of a diet high in saturated (milkderived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia2 . This was associated with a pro-inflammatory T helper type 1 (TH1) immune response and increased incidence of colitis in genetically susceptible Il102/2, but not wild-type mice. These effects are mediated bymilk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il102/2 mice. Together these data show that dietary fats, by promoting changesin host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. e low-fat purified mouse diet LF promoted Firmicutes, but also resulted in a lower abundance of most other phyla, whereas polyunsaturated (safflower oil) fat (PUFA) and saturated (milk-derived) fat diets (MF) resulted in a higher abundance of Bacteroidetes and a lower abundance of Firmicutes. Whereas MF (Monounsaturated Fat) and PUFA had similar effects on Bacteroidetes and Firmicutes, a significant bloom of a member of the Deltaproteobacteria, B. wadsworthia, was consistently observed only with MF. B. wadsworthia is a sulphite-reducing, immunogenic microbe that is difficult to detect in healthy individuals, but emerges under pathological conditions such as appendicitis and other intestinal inflammatory disorders We find the dependence of B. wadsworthia on diet-induced taurocholic acid intriguing and possibly representative of how certain gut microbes use bile to their advantage. Bile formation is unique to vertebrates, providing the host with the ability to digest and utilize a far greater variety of dietary substrates. Bile also has potent antimicrobial properties that can contribute to the selection or exclusion of many potential gut microbiota. However, several intestinal pathogens, including protozoa such as Giardia, Microsporidia and Cryptosporidia, and bacteria such as B. wadsworthia, H. hepaticus and Listeria monocytogenes, are not only bile-resistant, but highly favoured in the presence of bile21,22, possibly through suppression of symbiotic, commensal microorganisms, allowing pathobionts and pathogens an opportunity to establish a niche. Once established, the by-products of these bacteria, whether H2S or secondary bile acids, can serve as gut mucosal ‘barrier breakers’, allowing for increased immune-cell infiltration and thus acting synergistically with the bacterial antigenspecific immune response to induce tissue damage.
Diet rapidly and reproducibly alters the human gut microbiome <<– . Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes,Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals , reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease.
Gut Bacteria Might Guide The Workings Of Our Minds <<–found that the connections between brain regions differed depending on which species of bacteria dominated a person’s gut. That suggests that the specific mix of microbes in our guts might help determine what kinds of brains we have — how our brain circuits develop and how they’re wired.
Gut Microbiota from Twins Discordant for obesity modulate metabolism in mice In this paper, scientists removed bacteria from the guts of four pairs of human twins in which one was obese and the other was lean. The researchers then transplanted those microbes into the guts of lab mice who didn’t have any of their own microbes. It was found that the mice that got microbes from the obese twins gained more weight and accumulated more fat than those who got microbes from the lean twin, even when the mice ate identical diets. Differences in body composition were correlated with differences in fermentation of short-chain fatty acids (increased in Lean), metabolism of branched-chain amino acids (increased in Obese), and microbial transformation of bile acid species (increased in Lean and correlated with down-regulation of host farnesoid X receptor signaling). Cohousing Lean and Obese mice prevented development of increased adiposity and body mass in Obese cage mates and transformed their microbiota’s metabolic profile to a leanlike state. Transformation correlated with invasion of members of Bacteroidales from Lean (Ln) into Obese (Ob) microbiota. Invasion and phenotypic rescue were diet-dependent and occurred with the diet representing the lower tertile of U.S. consumption of saturated fats and upper tertile of fruits and vegetables but not with the diet representing the upper tertile of saturated fats and lower tertile of fruit and vegetable consumption. Collections generated from human microbiota samples can transmit donor phenotypes of interest (body composition and metabotypes) has a number of implications. Bottom line: Ridaura et al. ( 2) demonstrate that the microbiota from lean or obese humans induces similar phenotypes in mice and, more remarkably, that the microbiota from lean donors can invade and reduce adiposity gain in the obese-recipient mice if the mice are fed an appropriate diet. Analysis showed that members of the Bacteroidetes phylum, particularly Bacteroides spp., could pass from the Lean mice and colonize the Obese mice, suggesting that these bacteria were largely responsible for protection against increased adiposity. Lean twin–derived bacterial strains effectively colonized and ameliorated excess adiposity in Obch mice when the recipients were fed a low-fat, high-fi ber diet. This was not the case when the mice were fed a diet that was high in saturated fat but low in fiber. One of the main activities of the intestinal microbiota is to break down and ferment dietary fibers into short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. The host absorbs these acids, and humans obtain perhaps 5 to 10% of daily energy requirements from them. Ridaura et al. show that the microbiota in Lean mice produces greater amounts of SCFAs, particularly propionate and butyrate, and digests more of the plant fiber present in the mouse’s diet than the microbiota of Ob mice. Thus, increased weight gain in Ob mice does not result from increased energy harvest. Rather, the finding supports previous studies showing that although SCFAs are a source of energy, they promote leanness by inhibiting fat accumulation in adipose tissue, raising energy expenditure, and enhancing production of hormones associated with feelings of satiety. Other putative mechanisms include a role for the microbiota in metabolizing bile acids, branched-chain amino acids, and acylcarnitines, which have all been linked to either insulin resistance or obesity in humans and mice. Notably, a recent study showed that fecal transplants from lean individuals into obese counterparts improved insulin sensitivity in some obese recipients .
Dietary fiber is food for your gut bacteria. Too little fiber in your diet results in the bacteria eating your gut mucins that line your gut. When fed, the bacteria give us nutrients. Certain foods have positive effects. Garlic/Leeks have a lot of INULIN, which feeds actinobacter bacteria that are beneficial to us. Inulin is a prebiotic that feeds good bacteria. Garlic has antimicrobial properties taht help us out by diminishing harmful bacteria. Whole grain sources of fiber, however, are questionable in that they result in elevated levels of Prevotella spp. (Prevotella) that are associated with inflammation and increased incidence of Rheumatoid Arthritis. As for fermented foods, Kimchi, Sauerkraut, and yogurt, the jury is out, but they may be helpful.
Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression << Abstract: There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.
It has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic–pituitary–adrenal (HPA) axis response to stress , and anxiety behavior, which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression. Evidence suggests that probiotics can modulate the stress response and improve mood and anxiety symptoms in patients with chronic fatigue and irritable bowel syndrome. One such organism is Lactobacillus rhamnosus (JB-1), which has been demonstrated to modulate the immune system because it prevents the induction of IL-8 by TNF-α in human colon epithelial cell lines (T84 and HT- 29). This event was found to be mediated by connections of the gut and brain through the vagus nerve, which if cut, prevented the bacteria from causing emotional changes.
Postnatal microbial colonization programs HPA system for stress response in mice Absatract: Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic–pituitary–adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution withBifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.
Bygiene The New Paradigm of Bidirectional hygiene Abstract: The pervasive dogma surrounding the evolution of virulence – namely, that a pathogen’s virulence decreases over time to prevent threatening its host – is an archaic assertion that is more appropriately cast as an optimization of virulence cost and benefit. However, the prevailing attitudes underlying practices of medical hygiene and sanitization remain entrenched in these passé ideas. This is true despite the emergence of evidence linking those practices to mounting virulence and antimicrobial resistance in the hospital. It is, therefore, our position that just as the microbe has sought an optimized balance in virulence, so should we seek such an optimized balance in vigilance, complementing warfare with restoration. We call this approach “bygiene,” or bidirectional hygiene.
Gut Dysbiosis in Patients with Anorexia Abstract: Anorexia nervosa (AN) is a psychological illness with devastating physical consequences; however, its pathophysiological mechanism remains unclear. Because numerous reports have indicated the importance of gut microbiota in the regulation of weight gain, it is reasonable to speculate that AN patients might have a microbial imbalance, i.e. dysbiosis, in their gut. In this study, we compared the fecal microbiota of female patients with AN (n = 25), including restrictive (ANR, n = 14) and binge-eating (ANBP, n = 11) subtypes, with those of age-matched healthy female controls (n = 21) using the Yakult Intestinal Flora-SCAN based on 16S or 23S rRNA–targeted RT–quantitative PCR technology. AN patients had significantly lower amounts of total bacteria and obligate anaerobes including those from the Clostridium coccoides group, Clostridium leptum subgroup, and Bacteroides fragilis group than the age-matched healthy women. Lower numbers of Streptococcus were also found in the AN group than in the control group. In the analysis based on AN subtypes, the counts of the Bacteroides fragilis group in the ANR and ANBP groups and the counts of the Clostridium coccoides group in the ANR group were significantly lower than those in the control group. The detection rate of the Lactobacillus plantarum subgroup was significantly lower in the AN group than in the control group. The AN group had significantly lower acetic and propionic acid concentrations in the feces than the control group. Moreover, the subtype analysis showed that the fecal concentrations of acetic acid were lower in the ANR group than in the control group. Principal component analysis confirmed a clear difference in the bacterial components between the AN patients and healthy women. Collectively, these results clearly indicate the existence of dysbiosis in the gut of AN patients.
Normal Gut Microbiota modulates brain development and behavior <<– found that germ-free, unstressed mice were more active and more willing to explore exposed areas of a maze than mice that had normal gut microbiota. Like Sudo’s group, Heijtz and her colleagues were able to erase those behavioral differences by transplanting normal gut bacteria into the germ-free mice, but only if they did so while the mice were babies—again suggesting that there is a critical window for gut bacteria to establish normal patterns of behavior in its host animal.
Exposure to a Social Stressor Alters the Structure of the intestinal microbiota Abstract: Stressor exposure significantly changed the community structure of the microbiota, particularly when the microbiota were assessed immediately after stressor exposure. Most notably, stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio, and Dorea). In follow up experiments, mice were treated with an antibiotic cocktail to determine whether reducing the microbiota would abrogate the stressor-induced increases in circulating cytokines. Exposure to SDR failed to increase IL-6 and MCP-1 in the antibiotic treated mice. These data show that exposure to SDR significantly affects bacterial populations in the intestines, and remarkably also suggest that the microbiota are necessary for stressor-induced increases in circulating cytokines.
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.
Relton, J. K. & Rothwell, N. J. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res. Bull. 29, 243–246 (1992). The first study to report that inhibition of endogenous IL-1 limits neuronal death induced by cerebral ischaemia or excitotoxicity in vivo.
Prehn, J. H., Backhauss, C. & Krieglstein, J. Transforming growth factor-β 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J. Cereb. Blood Flow Metab. 13, 521–525 (1993). An early study showing neuroprotective effects of TGFβ in vivo against cerebral ischaemia, and in vitro against glu
Chao, C. C., Hu, S., Ehrlich, L. & Peterson, P. K. Interleukin-1 and tumor necrosis factor-α synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methylD-aspartate receptors. Brain. Behav. Immun. 9, 355–365 (1995). An early study showing interactions between cytokines to influence neuronal death in vitro, using human fetal brain cell cultures composed of neurons and glia.
Nawashiro, H., Martin, D. & Hallenbeck, J. M. Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J. Cereb. Blood Flow Metab. 17, 229–232 (1996). An early study indicating that endogenous TNFα mediates ischaemic brain damage in vivo. TNFbinding protein — a naturally occurring inhibitor of TNF — reduced damage caused by focal cerebral ischaemia in mice.
Scherbel, U. et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc. Natl Acad. Sci. USA 96, 8721–8726 (1999). This study might provide an explanation for seemingly conflicting reports indicating that endogenous TNFα is either neurotoxic (based largely on acute interventions) or neuroprotective (based largely on stadies on genetically modified animals). It reports that functional outcomes in TNFα-null mice were improved early after brain injury compared with wild type mice, but TNFα-null mice showed permanent deficits and reduced recovery.
Ferrari, D., Chiozzi, P., Falzoni, S., Hanau, S. & Di Virgilio, F. Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin. J. Exp. Med. 185, 579–582 (1997). An early study showing that IL-1β is released from microglia by activation of purinergic, P2X7 receptors. Bacterial LPS is required for activation of microglial IL-1β expression, whereas ATP induced cleavage and release.
Ohtsuki, T., Ruetzler, C. A., Tasaki, K. & Hallenbeck, J. M. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J. Cereb. Blood Flow Metab. 16, 1137–1142 (1996). The first demonstration that endogenous IL-1 can mediate ischaemic tolerance. Pre-treatment of gerbils three days before global ischaemia reduced brain injury. IL-1 was induced by a brief period of ‘preconditionary’ ischaemia.
Carrié, A. et al. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nature Genet. 23, 25–31 (1999). A direct link between one of the recently identified members of the IL-1/Toll receptor family in brain function. Cognitive function in patients with X-linked mental retardation is strongly associated with a nonsense mutation in a gene identified as IL-1-receptor-like protein (IL-1R AcPL).
Venters, H. D. et al. A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl Acad. Sci. USA 96, 9879–9884 (1999). This study provided a potential explanation for indirect effects of the proinflammatory cytokine TNFα on neuronal survival through modification of the signalling pathway of a protective growth factor, IGF. This mechanism might apply to other neurotoxic cytokines.
Loddick, S. A., MacKenzie, A. & Rothwell, N. J. An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. Neuroreport 7, 1465–1468 (1996). The first study reporting that inhibition of caspase activity protects against neuronal death (ischaemic brain damage) in vivo
Legos, J. J. et al. SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res. 892, 70–77 (2001). The first study to show that selective inhibition of p38 MAPK, which is involved in IL-1 and TNFα signalling,
Troy, C. M., Stefanis, L., Prochiantz, A., Greene, L. A. & Shelanski, M. L. The contrasting roles of ICE family proteases and interleukin-1β in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation. Proc. Natl Acad. Sci. USA 93, 5635–5640 (1996). An early study reporting the contribution of ICE (caspase 1) to apoptosis in a neuronal cell line (PC12 cells) and indicating that ICE acts through modification of superoxide dismutase 1.
Giulian, D., Woodward, J., Young, D. G., Krebs, J. F. & Lachman, L. B. Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularisation. J. Neurosci. 8, 2485–2490 (1988). One of the first reports of IL-1 actions on nerve cells that might be relevant to neurodegeneration and repair
6. Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy: from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 2005;1754:253-62 [CrossRef], [PubMed], [Web of Science ®]
7. Lee JC, Laydon JT, McDonnell PC, A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature1994;372:739-46 [CrossRef], [PubMed], [Web of Science ®]
8. Newton R, Holden N. Inhibitors of p38 mitogen-activated protein kinase: potential as anti-inflammatory agents in asthma? BioDrugs 2003;17:113-29 [CrossRef], [PubMed], [Web of Science ®]
9. Hale KK, Trollinger D, Rihanek M, Manthey CL. Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J Immunol 1999;162:4246-52 [PubMed], [Web of Science ®]
10. Beardmore VA, Hinton HJ, Eftychi C, Generation and characterization of p38 beta (MAPK11) gene-targeted mice. Mol Cell Biol 2005;25:10454-64 [CrossRef], [PubMed], [Web of Science ®]
11. Perregaux DG, Dean D, Cronan M, Inhibition of interleukin-1 beta production by SKF86002: evidence of two sites of in vitro activity and of a time and system dependence. Mol Pharmacol 1995;48:433-42 [PubMed], [Web of Science ®]
12. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001;81:807-69 [PubMed], [Web of Science ®]
13. Raingeaud J, Gupta S, Rogers JS, Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995;270:7420-26 [CrossRef],[PubMed], [Web of Science ®]
14. Sugden PH, Clerk A. Stress-responsive mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 1998;83:345-52 [CrossRef], [PubMed], [Web of Science ®]
15. Sweeney G, Somwar R, Ramlal T, An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. J Biol Chem 1999;274:10071-8[CrossRef], [PubMed], [Web of Science ®]
16. Heidenreich KA, Kummer JL. Inhibition of p38 mitogen-activated protein kinase by insulin in cultured fetal neurons. J Biol Chem 1996;271:9891-4 [CrossRef], [PubMed], [Web of Science ®]
17. Jiang Y, Gram H, Zhao M, Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem 1997;272:30122-8 [CrossRef], [PubMed], [Web of Science ®]
18. Hu MC, Wang YP, Mikhail A. Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines. J Biol Chem 1999;274:7095-102 [CrossRef], [PubMed], [Web of Science ®]
19. Cuenda A, Cohen P, Buee-Scherrer V, Goedert M. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J1997;16:295-305 [CrossRef], [PubMed], [Web of Science ®]
20. Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem 1998;273:1741-8 [CrossRef], [PubMed], [Web of Science ®]
21. Han J, Lee JD, Jiang Y, Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem1996;271:2886-91 [CrossRef], [PubMed], [Web of Science ®]
22. Stein B, Brady H, Yang MX, Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem 1996; 271:11427-33 [CrossRef], [PubMed], [Web of Science ®]
23. Moriguchi T, Kuroyanagi N, Yamaguchi K, A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem 1996;271:13675-9 [CrossRef], [PubMed], [Web of Science ®]
24. Moriguchi T, Toyoshima F, Gotoh Y, Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase Kinase 6 by osmotic shock, tumor necrosis factor-? and H2O2 J Biol Chem1996;271:26981-8 [CrossRef], [PubMed], [Web of Science ®]
25. Yamauchi J, Tsujimoto G, Kaziro Y, Itoh H. Parallel regulation of mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 in Gq-signaling cascade. J Biol Chem 2001;276:23362-72 [CrossRef], [PubMed], [Web of Science ®]
26. Bagrodia S, Dérijard B, Davis RJ, Cerione RA. Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J Biol Chem 1995;270:27995-8 [CrossRef], [PubMed], [Web of Science ®]
27. Zhang S, Han J, Sells MA, Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem 1995;270:23934-6 [CrossRef], [PubMed], [Web of Science ®]
28. Kim MS, Lee EJ, Kim HR, Moon A. p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res 2003;63:5454-61 [PubMed], [Web of Science ®]
29. Nick JA, Avdi NJ, Young SK, Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP. J Clin Invest 1997;99:975-86 [CrossRef], [PubMed], [Web of Science ®]
30. Zhang Y, Neo SY, Han J, RGS16 attenuates galphaq-dependent p38 mitogen-activated protein kinase activation by platelet-activating factor. J Biol Chem 1999;274:2851-7 [CrossRef], [PubMed], [Web of Science ®]
32. Hegen M, Gaestel M, Nickerson-Nutter CL, MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J Immunol 2006;177:1913-17 [CrossRef], [PubMed], [Web of Science ®]
33. Ben-Levy R, Hooper S, Wilson R, Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol 1998;8:1049-57 [CrossRef], [PubMed], [Web of Science ®]
34. Engel K, Kotlyarov A, Gaestel M. Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation. EMBO J 1998;17:3363-71 [CrossRef], [PubMed], [Web of Science ®]
35. McLaughlin MM, Kumar S, McDonnell PC, Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem 1996;271:8488-92 [CrossRef], [PubMed], [Web of Science ®]
39. Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science 1996;272:1347-9 [CrossRef], [PubMed], [Web of Science ®]
40. Yang SH, Galanis A, Sharrocks AD. Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Mol Cell Biol 1999;19:4028-37 [CrossRef], [PubMed], [Web of Science ®]
41. Vermeulen L, De Wilde G, Van Damme P, Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 2003;22:1313-24 [CrossRef], [PubMed], [Web of Science ®]
42. Song H, Ki SH, Kim SG, Moon A. Activating transcription factor 2 mediates matrix metalloproteinase-2 transcriptional activation induced by p38 in breast epithelial cells. Cancer Res 2006;66:10487-96 [CrossRef], [PubMed], [Web of Science ®]
43. Carter AB, Knudtson KL, Monick MM, The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). J Biol Chem 1999;274:30858-63 [CrossRef], [PubMed], [Web of Science ®]
44. Campbell J, Ciesielski CJ, Hunt AE, A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol 2004;173:6928-37 [CrossRef], [PubMed], [Web of Science ®]
45. Underwood DC, Osborn RR, Bochnowicz S, SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 2000;279:L895-902 [PubMed], [Web of Science ®]
46. Pietersma A, Tilly BC, Gaestel M, p38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level. Biochem Biophys Res Commun 1997;230:44-8 [CrossRef], [PubMed], [Web of Science ®]
47. Craxton A, Shu G, Graves JD, p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes. J Immunol 1998;161:3225-36 [PubMed], [Web of Science ®]
48. Ridley SH, Sarsfield SJ, Lee JC, Actions of IL-1 are selectively controlled by p38 mitogenactivated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol 1997;158:3165-73 [PubMed], [Web of Science ®]
49. Mbalaviele G, Anderson G, Jones A, Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther 2006;317:1044-53 [CrossRef], [PubMed], [Web of Science ®]
54. Sweeney SE, Firestein GS. Signal transduction in rheumatoid arthritis. Curr Opin Rheumatol 2001;16:231-7 [CrossRef]
55. Kumar S, Blake SM, Emery JG. Intracellular signaling pathways as a target for the treatment of rheumatoid arthritis. Curr Opin Pharmacol 2001;1:307-13 [CrossRef], [PubMed]
56. Badger AM, Bradbeer JN, Votta B, Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock, and immune function. J Pharmacol Exp Ther 1996;279:1453-61 [PubMed], [Web of Science ®]
57. Jackson JR, Bolognese B, Hillegass L, Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models. J Pharmacol Exp Ther 1998;284:687-92 [PubMed],[Web of Science ®]
58. Badger AM, Griswold DE, Kapadia R, Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 2000;43:175-83 [CrossRef], [PubMed], [Web of Science ®]
59. Wada Y, Nakajima-Yamada T, Yamada K, R-130823, a novel inhibitor of p38 MAPK, ameliorates hyperalgesia and swelling in arthritis models. Eur J Pharmacol 2005;506:285-95 [CrossRef], [PubMed], [Web of Science ®]
60. Wadsworth SA, Cavender DE, Beers SA, RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J Pharmacol Exp Ther 1999;291:680-7 [PubMed], [Web of Science ®]
61. Summers RW, Elliott DE, Qadir K, Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol 2003;98:2034-41 [CrossRef], [PubMed], [Web of Science ®]
62. Hollenbach E, Neumann M, Vieth M, Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. FASEB J 2004;18:1550-2 [PubMed], [Web of Science ®]
64. McDonald DR, Bamberger ME, Combs CK, Landreth GE. Beta-amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci 1998;18:4451-60 [PubMed], [Web of Science ®]
65. Legos JJ, Erhardt JA, White RF, SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res 2001;892:70-7 [CrossRef], [PubMed], [Web of Science ®]
66. Barone FC, Irving EA, Ray AM, SB 239063, a second-generation p38 mitogen activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J Pharmacol Exp Ther 2001;296:312-21 [PubMed], [Web of Science ®]
67. Barone FC, Irving EA, Ray AM, Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev 2001;21:129-45 [CrossRef], [PubMed], [Web of Science ®]
68. Koistinaho M, Kettunen MI, Goldsteins G, Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc Natl Acad Sci2002;99:1610-5 [CrossRef], [PubMed], [Web of Science ®]
69. Maroney AC, Finn JP, Connors TJ, Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem 2001;276:25302-8 [CrossRef], [PubMed], [Web of Science ®]
70. Rust W, Kingsley K, Petnicki T, Heat shock protein 27 plays two distinct roles in controlling human breast cancer cell migration on laminin-5. Mol Cell Biol Res Commun 1999;1:196-02 [CrossRef], [PubMed]
71. Simon C, Simon M, Vucelic G, The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. Exp Cell Res 2001;271:344-55 [CrossRef], [PubMed], [Web of Science ®]
72. Nemoto T, Kubota S, Ishida H, Ornithine decarboxylase, mitogen-activated protein kinase and matrix metalloproteinase-2 expressions in human colon tumors. World J Gastroenterol 2005;11:3065-9 [CrossRef], [PubMed], [Web of Science ®]
73. Davidson B, Givant-Horwitz V, Lazarovici P, Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): co-expression in metastatic serous ovarian carcinoma. Clin Exp Metastasis 2003;20:621-31 [CrossRef], [PubMed], [Web of Science ®]
74. Morooka T, Nishida E. Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells. J Biol Chem 1998;273:24285-8 [CrossRef], [PubMed], [Web of Science ®]
75. Junttila MR, Ala-Aho R, Jokilehto T, p38alpha and p38delta mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells. Oncogene 2007;26:5267-79 [CrossRef], [PubMed], [Web of Science ®]
76. Lim SJ, Lee YJ, Lee E. p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis. Oncol Rep 2006;16:1131-5 [PubMed], [Web of Science ®]
77. Guo X, Ma N, Wang J, Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer 2008;8:375 [CrossRef], [PubMed]
78. Yasui H, Hideshima T, Ikeda H, BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (HSP) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/HSP27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. Br J Haematol 2007;136:414-23 [CrossRef], [PubMed], [Web of Science ®]
79. Shin I, Kim S, Song H, H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. J Biol Chem 2005; 280: 14675-83 [CrossRef], [PubMed], [Web of Science ®]
81. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991;64:327-36 [CrossRef], [PubMed], [Web of Science ®]
82. Xu L, Chen S, Bergan RC. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 2006;25:2987-98 [CrossRef],[PubMed], [Web of Science ®]
83. Denkert C, Siegert A, Leclere A, An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. Clin Exp Metastasis 2002;19:79-85 [CrossRef], [PubMed], [Web of Science ®]
84. Johansson N, Ala-aho R, Uitto V, Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. J Cell Sci 2000;113:227-35 [PubMed], [Web of Science ®]
85. Han YC, Zeng XX, Wang R, Correlation of p38 mitogen-activated protein kinase signal transduction pathway to uPA expression in breast cancer. Ai Zheng 2007;26:48-53 [PubMed]
86. Zhou HY, Pon YL, Wong AS. Synergistic effects of epidermal growth factor and hepatocyte growth factor on human ovarian cancer cell invasion and migration: role of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. Endocrinology 2007;148:5195-208 [CrossRef], [PubMed], [Web of Science ®]
87. Simon C, Goepfert H, Boyd D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res 1998;58:1135-9 [PubMed], [Web of Science ®]
88. Yao J, Xiong S, Klos K, Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells. Oncogene 2001;20:8066-74 [CrossRef], [PubMed], [Web of Science ®]
89. She QB, Chen N, Dong Z. ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J Biol Chem 2000;275:20444-9 [CrossRef], [PubMed], [Web of Science ®]
90. She QB, Bode AM, Ma WY, Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res 2001;61:1604-10 [PubMed], [Web of Science ®]
92. Iyoda K, Sasaki Y, Horimoto M, Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer 2003;97:3017-26 [CrossRef], [PubMed], [Web of Science ®]
93. Corrèze C, Blondeau JP, Pomérance M. p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells. Eur J Endocrinol 2005;153:123-33 [CrossRef], [PubMed], [Web of Science ®]
94. Chang HL, Wu YC, Su JH, Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2. J Pharmacol Exp Ther 2008;325:841-9[CrossRef], [PubMed], [Web of Science ®]
95. Croons V, Martinet W, Herman AG, The protein synthesis inhibitor anisomycin induces macrophage apoptosis in rabbit atherosclerotic plaques through p38 mitogen-activated protein kinase. J Pharmacol Exp Ther 2009;329:856-64 [CrossRef],[PubMed], [Web of Science ®]
96. Elenitoba-Johnson KS, Jenson SD, Abbott RT, Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc Natl Acad Sci U S A 2003;100:7259-64[CrossRef], [PubMed], [Web of Science ®]
97. Karahashi H, Nagata K, Ishii K, Amano F. A selective inhibitor of p38 MAP kinase, SB202190, induced apoptotic cell death of a lipopolysaccharide-treated macrophage-like cell line, J774.1. Biochem Biophys Acta 2000;1502:207-23 [PubMed], [Web of Science ®]
98. Navas TA, Nguyen AN, Hideshima T, Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia2006;20:1017-27 [CrossRef], [PubMed], [Web of Science ®]
99. Lantos I, Bender PE, Razgaitis KA, Antiinflammatory activity of 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles. Isomeric 4-pyridyl and 4-substituted phenyl derivatives. J Med Chem 1984;27:72-5 [CrossRef], [PubMed], [Web of Science ®]
100. Saccani S, Pantano S, Natoli G. p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 2002;3:69-75 [CrossRef], [PubMed], [Web of Science ®]
101. Pargellis C, Tong L, Churchill L, Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol2002;9:268-72 [CrossRef], [PubMed]
104. Zack D, Campagnuolo GS, Middleton S, 66th American College of Rheumatology Annual Scientific Meeting, Orlando, 2003. J Clin Rheumatol 2002;8:207 [CrossRef], [PubMed]
105. Boehringer Ingelheim Pharmaceuticals Inc. Method for administering BIRB 796 BS. WO/2003/049742; 2003
106. Hill RJ, Dabbagh K, Phippard D, Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther 2008;327:610-9 [CrossRef], [PubMed], [Web of Science ®]
107. Kim ES, Kim MS, Moon A. Transforming growth factor (TGF)-beta in conjunction with H-ras activation promotes malignant progression of MCF10A breast epithelial cells. Cytokine 2005;21(29):84-91 [CrossRef]
108. Kim ES, Kim MS, Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 2004;25:1375-82 [PubMed], [Web of Science ®]
109. Kim ES, Sohn YW, Moon A. TGF-beta-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett 2007;252:147-56 [CrossRef], [PubMed], [Web of Science ®]
110. Song H, Moon A. Glial cell-derived neurotrophic factor (GDNF) promotes low-grade Hs683 glioma cell migration through JNK, ERK-1/2 and p38 MAPK signaling pathways. Neurosci Res 2006;56:29-38 [CrossRef], [PubMed], [Web of Science ®]
111. Dominguez C, Powers DA, Tamayo N. p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel 2005;8:421-30 [PubMed], [Web of Science ®]
112. Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem 2005;12:2979-94 [CrossRef], [PubMed], [Web of Science ®]
113. Mongin-Bulewski C. Drug Discovery Technology 2002 (Part V) – Overnight Report. Boston MA, USA. IDdb Meeting Report. 4-9 August 2002
114. Gruenbaum LM, Schwartz R, Woska JR, Inhibition of pro-inflammatory cytokine production by the dual p38/JNK2 inhibitor BIRB796 correlates with the inhibition of p38 signaling. Biochem Pharmacol 2009;77:422-32 [CrossRef], [PubMed], [Web of Science ®]
115. Branger J, van den Blink B, Weijer S, Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. Blood 2003;101:4446-8 [CrossRef], [PubMed], [Web of Science ®]
116. Schreiber S, Feagan B, D’Haens G, Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006;4:325-34 [CrossRef], [PubMed],[Web of Science ®]
117. Cohen SB, Cheng TT, Chindalore V, Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum 2009;60:335-44[CrossRef], [PubMed], [Web of Science ®]
118. Alten RE, Zerbini C, Jeka S, Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis 2009: published online 8 Apr 2009, doi:10.1136/ard.2008.104802
119. Pusztai L, Mendoza TR, Reuben JM, at al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 2004;25:94-102 [CrossRef], [PubMed], [Web of Science ®]
120. Fijen JW, Zijlstra JG, De Boer P, Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin Exp Immunol 2001;124:16-20 [CrossRef],[PubMed], [Web of Science ®]
121. Behr TM, Berova M, Doe CP, p38 mitogen-activated protein kinase inhibitors for the treatment of chronic cardiovascular disease. Curr Opin Investig Drugs 2003;4:1059-64 [PubMed]
122. Braddock M. Inflammation in drug discovery and development SRI’s seventh international meeting. San Diego, CA, USA. IDdb Meeting Report. 20-21 February 2003
123. GlaxoSmithKline. P38 mitogen-activated protein (MAP) kinase inhibitor (SB681323) study in patients with neuropathic pain. ClinicalTrials.gov, Bethesda, MD: National Library of Medicine. Available from:http://www.clinicaltrials.gov/ct2/show/NCT00390845 [Last accessed May 2009]
127. Genovese MC, Cohen SB, Wofsy D, A randomized, double-blind, placebo-controlled phase 2 study of an oral p38 alpha MAPK inhibitor, SCIO-469, in patients with active rheumatoid arthritis. San Francisco: 72th American College of Rheumatology Annual Scientific Meeting, 24-29 October 2008
129. Weisman M, Furst D, Schiff M, A double-blind, placebo controlled trial of VX-745, an oral p38 mitogen-activated protein kinase (MAPK) inhibitor in patients with rheumatoid arthritis(RA). FRI0018. Stockholm: European League Against Rheumatism, Annual Congress, Jun 12-15, 2002
130. Vertex Pharmaceuticals Inc. Vertex moves to re-allocate resources from VX-745 in p38MAP kinase program to accelerate development of second generation drug candidates VX-702 and VX-850. Press Release 2001
131. Vertex Pharmaceuticals Inc. Preliminary Phase IIa data for VX-702 demonstrate tolerability and reduction in C-reactive protein in cardiovascular patients. Rome: European Society of Cardiology’s Acute Cardiac Care Symposium, 17-20 October 2004
132. Damjanov N, Kauffman R, Spencer-Green GT. Safety and efficacy of VX-702, a p38 MAP kinase inhibitor, in rheumatoid arthritis. OP-0246. Paris: European League Against Rheumatism, Annual Congress, Jun 11-14, 2008
133. Damjanov N, Kauffman R, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: Results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum2009;60:1232-41 [CrossRef], [PubMed], [Web of Science ®]
134. Wang Y, Singh R, Lefkowitch JH, Tumor necrosis factor-induced toxic liver injury results from JNK2 dependent activation of caspase-8 and the mitochondrialdeath pathway. J Biol Chem 2006;281:15258-67 [CrossRef], [PubMed], [Web of Science ®]
135. Muniyappa H, Das KC. Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism. Cell Signal 2008;20:675-83 [CrossRef], [PubMed], [Web of Science ®]
136. Heinrichsdorff J, Luedde T, Perdiguero E, p38alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep 2008;9:1048-54 [CrossRef], [PubMed], [Web of Science ®]
137. Whitmarsh AJ, Yang SH, Su MS, Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol 1997;17:2360-71 [PubMed], [Web of Science ®]
139. Ventura JJ, Tenbaum S, Perdiguero E, p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet 2007;39:750-8 [CrossRef], [PubMed], [Web of Science ®]
140. Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov 2009;8:480-99 [CrossRef], [PubMed], [Web of Science ®]
141. Ronkina N, Kotlyarov A, Dittrich-Breiholz O, The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK. Mol Cell Biol2007;27:170-81 [CrossRef], [PubMed], [Web of Science ®]
142. Ananieva O, Darragh J, Johansen C, The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol 2008;9:1028-36 [CrossRef], [PubMed], [Web of Science ®]
143. Brook M, Tchen CR, Santalucia T, Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol2006;26:2408-18 [CrossRef], [PubMed], [Web of Science ®]
145. Mayer RJ, Callahan JF. p38 MAP kinase inhibitors: a future therapy for inflammatory diseases. Drug Discov Today2006;3:49-54 [CrossRef]
 van Marum, R. J., Current and future therapy in Alzheimer’s disease. Fundam. Clin. Pharmacol. 2008, 22, 265–274.  Morales, I., Guzman-Mart ´ ´ınez, L., Cerda-Troncoso, C., Far´ıas, G. A. et al., Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014, 8, 112.  Hu, N., Yu, J. T., Tan, L., Wang, Y. L. et al., Nutrition and the risk of Alzheimer’s disease. Biomed. Res. Int. 2013, 2013, 524820.  Lin, C. C., Hsu, Y. F., Lin, T. C., Effects of punicalagin and punicalin on carrageenan-induced inflammation in rats. Am. J. Chin. Med. 1999, 27, 371–376.  Adams, L. S., Seeram, N. P., Aggarwal, B. B., Takada, Y. et al., Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J. Agric. Food. Chem. 2006, 54, 980–985.  Xu, X., Yin, P., Wan, C., Chong, X. et al., Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-B activation. Inflammation 2014, 37, 956–965.  Bhatia, H. S., Candelario-Jalil, E., de Oliveira, A. C., Olajide, O. A. et al., Mangiferin inhibits cyclooxygenase-2 expression and prostaglandin E2 production in activated rat microglial cells. Arch. Biochem. Biophys. 2008, 477, 253–258.  Olajide, O. A., Bhatia, H. S., de Oliveira, A. C., Wright, C. W. et al., Inhibition of neuroinflammation in LPS-activated microglia by cryptolepine. Evid. Based Complement Alternat. Med. 2013, 2013, 459723. Vinet, J., Weering, H. R., Heinrich, A., Kalin, R. E. et al., Neu- ¨ roprotective function for ramified microglia in hippocampal excitotoxicity. J. Neuroinflammation 2012, 9, 27.  Olajide, O. A., Velagapudi, R., Okorji, U. P., Sarker, S. D. et al., Picralima nitida seeds suppress PGE2 production by interfering with multiple signalling pathways in IL-1-stimulated SKN-SH neuronal cells. J. Ethnopharmacol. 2014, 152, 377–383.  Fiebich, B. L., Lieb, K., Engels, S., Heinrich, M., Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J. Neuroimmunol. 2002, 132, 18–24.  Munoz, L., Ammit, A. J., Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 2010, 58, 561–568.  Winand, J., Schneider, Y. J., The anti-inflammatory effect of a pomegranate husk extract on inflamed adipocytes and macrophages cultivated independently, but not on the inflammatory vicious cycle between adipocytes and macrophages. Food Funct. 2014, 5, 310–318.  Kudo, I., Murakami, M., Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. J. Biochem. Mol. Biol. 2005, 38, 633–638.  Wang, J., Limburg, D., Carter, J., Mbalaviele, G. et al., Selective inducible microsomal prostaglandin E(2) synthase- 1 (mPGES-1) inhibitors derived from an oxicam template. Bioorg. Med. Chem. Lett. 2010, 20, 1604–1609.  Baeuerle, P. A., Baltimore, D., NF-kappa B: ten years after. Cell. 1996, 87, 13–20.  Huang, C. Y., Fujimura, M., Noshita, N., Chang, Y. Y. et al., SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2001, 21, 163–173.  Zhang, W., Potrovita, I., Tarabin, V., Herrmann, O. et al., Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia. J. Cereb. Blood Flow Metab. 2005, 25, 30– 40.  Gu, J. H., Ge, J. B., Li, M, Wu, F. et al., Inhibition of NF- B activation is associated with anti-inflammatory and antiapoptotic effects of Ginkgolide B in a mouse model of cerebral ischemia/reperfusion injury. Eur. J. Pharm. Sci. 2012, 47, 652–660.  Sastre, M., Walter, J., Gentleman, S. M., Interactions between APP secretases and inflammatory mediators. J. Neuroinflammation 2008, 5, 25.  Gong, P., Xu, X., Shi, J., Ni, L. et al., Phosphorylation of mitogen- and stress-activated protein kinase-1 in astrocytic inflammation: a possible role in inhibiting production of in- flammatory cytokines. PLoS One 2013, 8, e81747.  Yong, H. Y., Koh, M. S., Moon, A., The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin. Investig. Drugs 2009, 18, 1893.  Liu, S. L., Kielian, T., Microglial activation by Citrobacter koseri is mediated by TLR4-and MyD88-dependent pathways. J. Immunol. 2009, 183, 5537–5547.  Butler, M. P., Hanly, J. A., Moynagh, P. N., Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-de
Pelvic congestion syndrome (PCS) is characterized by chronic pelvic discomfort exacerbated by prolonged standing and coitus in women who have periovarian varicosities on imaging studies. The etiology of PCS is unclear and the optimum treatment is uncertain. It primarily affects multiparous women in the reproductive age group and no cases have occurred in menopausal women.
The most commonly made diagnosis in chronic pelvic pain is endometriosis (31%). The majority are undiagnosed or improperly diagnosed. In the majority of women with no obvious pathological cause for their pain, they may be suffering from pelvic congestion syndrome (PCS) instead. PCS accounts for up to 30% of patients presenting with chronic pelvic pain and is characterized by symptoms of dysmenorrhea, dysuria, and dyspareunia. PCS also carries a psychological burden and is often found in conjunction with increased levels of anxiety, stress, and depression. It can often be found in conjunction with vulvar and pelvic varices in women and with varicoceles in men. Many patients will present with chronic, dull, lower abdominal pain often accompanied by dyspareunia and bladder irritability and urgency. The pain is typically relieved by lying down and exacerbated by standing up or increased intra-abdominal pressure, such as during pregnancy and the premenstrual period. Pain during intercourse or during the postcoital period is not uncommon.
Differential diagnosis in chronic pelvic pain is lengthy and includes pelvic inflammatory disease, endometriosis, pelvic tumors, interstitial cystitis, and inflammatory bowel disease
It has been found that there is gross dilatation, incompetence, and reflux of the ovarian veins in women with PCS. Anatomic and hormonal factors lead to venous insufficiency of the ovarian veins and/or internal iliac veins, resulting in periovarian pelvic varicosities, thus producing pelvic venous congestion. Ovarian vein dilatation, stasis, and/or reflux on pelvic venography are common findings in multiparous premenopausal women but only some have symptoms. The use of venoconstrictors or ovarian vein ligation has produced relief of pain in some patients. Studies using Dihydroergotamine during an acute attack demonstrated relief of pain when the veins in the pelvis constrict. (Lancet. 1987;2(8555):351) Multiparous women (who have had multiple pregnancies) have a higher prevelance of PCS due to the 50% increase in vascular congestion that occurs in pregnancy, leading to venous incompetence and reflux in the non-pregnant state and thus pain.
Extrinsic compression of the left renal vein between the aorta and superior mesenteric artery leads to an increase incidence of PCS on the left side of the pelvis. This results in left flank pain, hematuria, and pelvic congestion. It has been noted that the left ovarian veins have no valves, increasing congestion on the left side as well.
Menopause decreases the incidence of PCS because estrogen acts as a venodilator and of course is no longer present after menopause.
Examination will show tenderness on abdominal examination over the adnexa and history of postcoital aching pain. Ultrasound may show incompetent and dilated ovarian veins which are common but nonspecific findings. Also, dilatation of the left ovarian vein with reversed caudal flow, presence of tortuous and dilated pelvic venous plexuses, and dilated arcuate veins crossing the uterine myometrium are found in PCS with increased diameters of the left ovarian vein at 7.9 mm (usual is 5.4 mm).
Selective ovarian and internal iliac venography through catheterization of the right and left ovarian veins via a percutaneous femoral or jugular approach demonstrate abnormally dilated ovarian veins (>10 mm in diameter), sluggish blood flow, reflux causing retrograde fill and congestion of the ovarian venous plexus in PCS. Up to 80 % of premenopausal women are found to have pelvic varicosities and venous stasis.
Computed tomography (CT) and magnetic resonance (MR) imaging identify tortuous, dilated pelvic and ovarian veins, broad ligament vascular congestion, and ovarian varicoceles better than ultrasound imaging. A growing body of data suggests that magnetic resonance venography (MRV) and CT scan are just as useful as pelvic Ultrasound.
Treatment of PCS consists of hormone therapy, embolotherapy, sclerotherapy, and endovascular and open surgery
First options are medical treatment using Goserelin, Medroxyprogesterone acetate, or etongestrel implants to hormonally treat the vascular congestion.
Invasive therapies that are successful include procedures such as embolization or sclerotherapy of the ovarian veins with or without the internal iliac veins. This involves interventional radiology:
Edwards RD, Robertson IR, MacLean AB, Hemingway AP. Case report: pelvic pain syndrome – successful treatment by ovarian vein embolization. Clin Radiol. 1993;47:429-431.
14. Kindgen-Milles D, Arndt JO. Nitric oxide as a chemical link in the generation of pain from veins in humans. Pain. 1996;64:139-142.
13. Stones RW, Thomas DC, Beard RW. Suprasensitivity to calcitonin gene-related peptide but not vasoactive intestinal peptide in women with chronic pelvic pain. Clin Auton Res. 1992;2:343- 348.
12. Stones RW, Vials A, Milner P, Beard RW, Burnstock G. Release of vasoactive agents from the isolated perfused human ovary. Eur J Obstet Gynecol Reprod Biol. 1996;67:191-196.
Beard RW, Reginald PW, Pearce S. Psychological and somatic factors in women with pain due to pelvic congestion. Adv Exp Biol Med. 1988;245:413-421.
Allen WA. Chronic pelvic congestion and pelvic pain. Am J Obstet Gynecol. 1971:109:198-202.
Capasso P, Simons C, Trotteur g, Dondelinger RF, Henroteaux D, Gaspard U. Treatment of symptomatic pelvic varices by ovarian vein embolization. Cardiovasc Intervent Radiol. 1997:20:107-111.
Kim HS, Malhotra AD, Rowe PC, Lee JM, Venbrux AC. Embolotherapy for pelvic congestion syndrome: long-term results. J Vasc Interv Radiol 2006;17(Pt 1):289-97.
Soysal ME, Soysal S, Vicdan K, Ozer S. A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion. Hum Reprod 2001;16:931-9.
Kim KW, Cho JY, Kim SH, Yoon JH, Kim DS, Chung JW, et al. Diagnostic value of computed tomographic findings of nutcracker syndrome: correlation with renal venography and renocaval pressure gradients. Eur J Radiol 2011;80:648-54.
Malgor RD, Labropoulos N. Diagnosis of venous disease with duplex ultrasound. Phlebology 2013;28(Suppl 1):158-61.
Asciutto G, Asciutto KC, Mumme A, Geier B. Pelvic venous incompetence: reflux patterns and treatment results. Eur J Vasc Endovasc Surg 2009;38:381-6.
Kurklinsky AK, Rooke TW. Nutcracker phenomenon and nutcracker syndrome. Mayo Clin Proc 2010;85:552-9.
Asciutto G, Mumme A, Marpe B, Koster O, Asciutto KC, Geier B. MR venography in the detection of pelvic venous congestion. Eur J Vasc Endovasc Surg 2008;36:491-6.
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