Genetic Marker for Stroke and Cardiovascular Disease – Folate and Vit B12 pathways

Researchers Discover Underlying Genetic Marker for Stroke and Cardiovascular Disease

NIH-funded findings point to new potential strategies for disease prevention and treatment.

Scientists studying the genomes of nearly 5,000 people have pinpointed a genetic variant tied to an increased risk for stroke, and have also uncovered new details about an important metabolic pathway that plays a major role in several common diseases. Together, their findings may provide new clues to underlying genetic and biochemical influences in the development of stroke and cardiovascular disease, and may also help lead to new treatment strategies.

“Our findings have the potential to identify new targets in the prevention and treatment of stroke, cardiovascular disease and many other common diseases,” said Stephen R. Williams, Ph.D., a postdoctoral fellow at the University of Virginia Cardiovascular Research Center and the University of Virginia Center for Public Health Genomics, Charlottesville.

Dr. Williams, Michele Sale, Ph.D., associate professor of medicine, Brad Worrall, M.D., professor of neurology and public health sciences, all at the University of Virginia, and their team reported their findings March 20, 2014 in PLoS Genetics. The investigators were supported by the National Human Genome Research Institute (NHGRI) Genomics and Randomized Trials Network (GARNET) program.

This image shows a group of people with GTCA written above them.

Researchers supported by NHGRI’s Genomics and Randomized Trials Network (GARNET) program, who have been studying the genomes of nearly 5,000 people, have pinpointed a genetic variant tied to increased risk for stoke and cardiovascular disease. Credit Jonathan Bailey, NHGRI.

Stroke is the fourth leading cause of death and a major cause of adult disability in this country, yet its underlying genetics have been difficult to understand. Numerous genetic and environmental factors can contribute to a person having a stroke. “Our goals were to break down the risk factors for stroke,” Dr. Williams said.

The researchers focused on one particular biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. They knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia. Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when.

But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels – and methionine metabolism gone awry – are not well defined.

Dr. Williams and his colleagues conducted genome-wide association studies of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism – the ability to convert methionine to homocysteine – in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.

In a genome-wide association study, researchers scan the genome to identify specific genomic variants associated with a disease. In this case, the scientists were trying to identify variants associated with a trait – the ability to metabolize methionine into homocysteine.

Investigators identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine. They found that among the five genes, one – the ALDH1L1 gene – was also strongly associated with stroke in the Framingham study. When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival.

They also made important discoveries about the methionine-homocysteine process. “GNMT produces a protein that converts methionine to homocysteine. Of the five genes that we identified, it was the one most significantly associated with this process,” Dr. Williams said. “The analyses suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.”

“It’s striking that the genes are in the same pathway, so we know that the genomic variants affecting that pathway contribute to the variability in disease and risk that we’re seeing,” he said. “We may have found how genetic information controls the regulation of GNMT.”

The group determined that the five genes accounted for 6 percent of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13 percent of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk. In many complex diseases, genomic variants often account for less than 5 percent of such differences.

“This is a great example of the kinds of successful research efforts coming out of the GARNET program,” said program director Ebony Madden, Ph.D. “GARNET scientists aim to identify variants that affect treatment response by doing association studies in randomized trials. These results show that variants in genes are associated with the differences in homocysteine levels in individuals.”

The association of the ALDH1L1 gene variant with stroke is just one example of how the findings may potentially lead to new prevention efforts, and help develop new targets for treating stroke and heart disease, Dr. Williams said.

“As genome sequencing becomes more widespread, clinicians may be able to determine if a person’s risk for abnormally high levels of homocysteine is elevated,” he said. “Changes could be made to an individual’s diet because of a greater risk for stroke and cardiovascular disease.”

The investigators plan to study the other four genes in the pathway to try to better understand their potential roles in stroke and cardiovascular disease risk.

NOTES ABOUT THIS GENETICS RESEARCH

In addition to NHGRI, the research was supported by funds from the National Heart, Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging and the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine.

The National Human Genome Research Institute is one of the 27 institutes and centers at the National Institutes of Health. The NHGRI Extramural Research Program supports grants for research and training and career development at sites nationwide.

Contact: Press Office – National Human Genome Research Institute/NIH
Source:National Human Genome Research Institute/NIH press release.


 

Methionine

Although mammals cannot synthesize methionine, they can still use it in a variety of biochemical pathways:

Catabolism

Methionine is converted to S-adenosylmethionine (SAM) by (1) methionine adenosyltransferase.

SAM serves as a methyl-donor in many (2) methyltransferase reactions, and is converted to S-adenosylhomocysteine (SAH).

(3) Adenosylhomocysteinase converts SAH to homocysteine.

There are two fates of homocysteine: it can be used to regenerate methionine, or to form cysteine.

Regeneration

Methionine can be regenerated from homocysteine via (4) methionine synthase in a reaction that requires Vitamin B12 as a cofactor.

Homocysteine can also be remethylated using glycine betaine (NNN-trimethyl glycine, TMG) to methionine via the enzyme betaine-homocysteine methyltransferase (E.C.2.1.1.5, BHMT). BHMT makes up to 1.5% of all the soluble protein of the liver, and recent evidence suggests that it may have a greater influence on methionine and homocysteine homeostasis than methionine synthase.

Reverse-transulfurylation pathway: conversion to cysteine[edit]

Homocysteine can be converted to cysteine.

Ethylene synthesis

This amino acid is also used by plants for synthesis of ethylene. The process is known as the Yang Cycle or the methionine cycle.

The Yang cycle

Chemical synthesis

Racemic methionine can be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation.[17]

Human nutrition

Requirements

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For methionine combined with cysteine, for adults 19 years and older, 19 mg/kg body weight/day.[18]

Dietary sources

Food sources of Methionine[19]
Food g/100g
Egg, white, dried, powder, glucose reduced 3.204
Sesame seeds flour (low fat) 1.656
Egg, whole, dried 1.477
Cheese, Parmesan, shredded 1.114
Brazil nuts 1.008
Soy protein concentrate 0.814
Chicken, broilers or fryers, roasted 0.801
Fish, tuna, light, canned in water, drained solids 0.755
Beef, cured, dried 0.749
Bacon 0.593
Beef, ground, 95% lean meat / 5% fat, raw 0.565
Pork, ground, 96% lean / 4% fat, raw 0.564
Wheat germ 0.456
Oat 0.312
Peanuts 0.309
Chickpea 0.253
Corn, yellow 0.197
Almonds 0.151
Beans, pinto, cooked 0.117
Lentils, cooked 0.077
Rice, brown, medium-grain, cooked 0.052

High levels of methionine can be found in eggs, sesame seeds, Brazil nuts, fish, meats and some other plant seeds; methionine is also found in cereal grains. Most fruits and vegetables contain very little of it. Most legumes are also low in methionine. However, it is the combination of methionine and lysine which is considered for completeness of a protein.[20] Racemic methionine is sometimes added as an ingredient to pet foods.[21]

Restriction

There is scientific evidence that restricting methionine consumption can increase lifespans in fruit flies.[22]

A 2005 study showed methionine restriction without energy restriction extends mouse lifespan.[23]

A study published in Nature showed adding just the essential amino acid methionine to the diet of fruit fliesunder dietary restriction, including restriction of essential amino acids (EAAs), restored fertility without reducing the longer lifespans that are typical of dietary restriction, leading the researchers to determine that methionine “acts in combination with one or more other EAAs to shorten lifespan.”[22][24][25] Restoring methionine to the diet of mice on a dietary restriction regimen blocks many acute benefits of dietary restriction, a process that may be mediated by increased production of hydrogen sulfide.[26]

Several studies showed that methionine restriction also inhibits aging-related disease processes in mice[27][28] and inhibits colon carcinogenesis in rats.[29] In humans, methionine restriction through dietary modification could be achieved through a vegan diet. Veganism being a completely plant based diet is typically very low in methionine, however certain nuts and legumes may provide higher levels.[30]

A 2009 study on rats showed “methionine supplementation in the diet specifically increases mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its hepatotoxicity“.[31]

However, since methionine is an essential amino acid, it cannot be entirely removed from animals’ diets without disease or death occurring over time[citation needed]. For example, rats fed a diet without methionine and choline developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks. Administration of methionine ameliorated the pathological consequences of methionine deprivation.[32] Short-term removal of only methionine from the diet can reverse diet-induced obesity and promotes insulin sensitivity in mice.[33]

Methionine might also be essential to reversing damaging methylation of glucocorticoid receptors caused by repeated stress exposures, with implications for depression.[34]

Health

Loss of methionine has been linked to senile greying of hair. Its lack leads to a buildup of hydrogen peroxide in hair follicles, a reduction in tyrosinase effectiveness, and a gradual loss of hair color.[35]

Methionine is an intermediate in the biosynthesis of cysteinecarnitinetaurinelecithinphosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis.[

Risk factors for women with heart disease

women-cvd-under-55-and-over-55-p2women-cvd-under-55-and-over-55

women CVD under 55 and over 55 p3.JPG

Heart disease risk factors for women

Although several traditional risk factors for coronary artery disease — such as high cholesterol, high blood pressure and obesity — affect women and men, other factors may play a bigger role in the development of heart disease in women. For example, risk factors may include:

  • Diabetes. Women with diabetes are at greater risk of heart disease than are men with diabetes.
  • Mental stress and depression. Women’s hearts are affected by stress and depression more than men’s. Depression makes it difficult to maintain a healthy lifestyle and follow recommended treatment, so talk to your doctor if you’re having symptoms of depression.
  • Smoking. In women, smoking is a greater risk factor for heart disease in women than it is in men.
  • Inactivity. A lack of physical activity is a major risk factor for heart disease, and some research has found women to be more inactive than men.
  • Menopause. Low levels of estrogen after menopause pose a significant risk factor for developing cardiovascular disease in the smaller blood vessels (coronary microvascular disease).
  • Broken heart syndrome. This condition — often brought on by stressful situations that can cause severe, but usually temporary, heart muscle failure — occurs more commonly in women after menopause. This condition may also be called takotsubo cardiomyopathy, apical ballooning syndrome or stress cardiomyopathy.
  • Pregnancy complications. High blood pressure or diabetes during pregnancy can increase women’s long-term risk of high blood pressure and diabetes and increase the risk of development of heart disease in the mothers.

    Some research has found that if you had pregnancy complications such as high blood pressure or diabetes your children may also have an increased risk of heart disease in the future.

Decreased bone mineral density (BMD) leads to increased risk of cardiovascular (CV) disease

A study to optimise bone strength and reducing risk of fracture, while at the same time decreasing risk of cardiovascular disease was done by the following team:

1Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, USA
2Cleveland Clinic Foundation, Center for Functional Medicine, Cleveland, Ohio, USA
3Center for Primary Health Care Research, Department of Clinical Sciences, Faculty of Medicine at Lund University, Malmö, Sweden
4Emeritus Professor of Nutritional Science, Colorado State University, Fort Collins, Colorado, USA
Correspondence to Dr James H O’Keefe; gro.sekul-tnias@efeekoj

The majority of Americans do not consume the current recommended dietary allowance for calcium, and the lifetime risk of osteoporosis is about 50%. However, traditional mononutrient calcium supplements may not be ideal. We comprehensively and systematically reviewed the scientific literature in order to determine the optimal dietary strategies and nutritional supplements for long-term skeletal health and cardiovascular health. To summarise, the following steps may be helpful for building strong bones while maintaining soft and supple arteries: (1) calcium is best obtained from dietary sources rather than supplements; (2) ensure that adequate animal protein intake is coupled with calcium intake of 1000 mg/day; (3) maintain vitamin D levels in the normal range; (4) increase intake of fruits and vegetables to alkalinise the system and promote bone health; (5) concomitantly increase potassium consumption while reducing sodium intake; (6) consider increasing the intake of foods rich in vitamins K1 and K2; (7) consider including bones in the diet; they are a rich source of calcium-hydroxyapatite and many other nutrients needed for building bone.

Keywords: QUALITY OF CARE AND OUTCOMES, CV RISK, CALCIUM, VITAMIN D

Key questions

What is already known about this subject?

  • The lifetime risk of osteoporosis is approximately 50%. Most people do not consume the Recommended Daily Allowance of calcium. Traditional mononutrient calcium supplements may not be ideal for promoting long-term cardiovascular and skeletal health.

What does this study add?

  • Calcium is ideally obtained from dietary sources. The form of calcium in bones and bone meal is calcium-hydroxyapatite, which may be particularly effective for building bone.

How might this impact on clinical practice?

  • Increased consumption of calcium-rich foods such as bones, fermented dairy products (e.g. yogurt, kefir, cheese), leafy greens, almonds, and chia seeds may be effective for improving both skeletal and cardiovascular health.

Introduction

Calcium: general physiology and epidemiology

Calcium is the most ubiquitous mineral in the human body. An average-sized adult body contains approximately 1000 to 1200 g of calcium, which is predominately incorporated into bones and teeth in the form of calcium-hydroxyapatite (Ca10(PO4)6(OH)2) crystals. The remainder circulates throughout the blood and soft tissues, and plays fundamental roles in cell conduction, muscle function, hormone regulation, vitamin (Vit) K-dependent pathways, and cardiac and blood vessel function.1

Some studies indicate only 30% of the US population consumes the Recommended Dietary Allowance of calcium, which is 1000–1200 mg daily.1 Furthermore, humans absorb only about 30% of calcium from foods depending on the specific source.1 The body will demineralise its own skeletal system to maintain serum calcium levels in situations where dietary calcium is insufficient and/or absorption is decreased, and/or excretion is increased.2

Osteopenia/osteoporosis: an epidemic

Starting at about age 50 years, postmenopausal women lose about 0.7–2% of their bone mass each year, while men over age 50 years lose 0.5–0.7% yearly. Between ages 45 and 75 years, women, on average, lose 30% of their bone mass, whereas men lose 15%.

According to the US Surgeon General’s Report, 1 in 2 Americans over age 50 years is expected to have or to be at risk of developing osteoporosis.3 Osteoporosis causes 8.9 million fractures annually, with an estimated cumulative cost of incident fractures predicted at US$474 billion over the next 20 years in the USA.3–6 Among adult women over age 45 years, osteoporosis accounts for more days spent in hospital than many other diseases such as diabetes, myocardial infarction (MI), chronic obstructive airway disease and breast cancer.3 Fragility fractures are the primary cause of hospitalisation and/or death for US adults ≥ age 65 years and older; and 44% of nursing home admissions are due to fractures.3

A Mayo Clinic study reported that compared to 30 years ago, forearm fractures have risen more than 32% in boys and 56% in girls. The authors concluded that dietary changes, including insufficient calcium and excess phosphate, were significantly associated with increased fractures.7 Public health approaches are crucial to prevent symptomatic bone disease, but widespread pharmacological prophylaxis is prohibitively expensive and carries potential serious adverse effects.

Cardiovascular disease and bone mineral disease: a calcium nexus

Strong epidemiological associations exist between decreased bone mineral density (BMD) and increased risk of both cardiovascular (CV) disease and CV death.8 For example, individuals with osteoporosis have a higher risk of coronary artery disease, and vice versa. This problem will be magnified if the therapies for osteoporosis (eg, calcium supplements) independently increase risk of MI.

Magnesium

Maintaining replete magnesium status may reduce risk for the metabolic syndrome, diabetes, hypertension and MI.30 Circumstantial and experimental evidence has also implicated magnesium deficiency in osteoporosis.31–34 Optimal dietary magnesium intake is about 7–10 mg/kg/day, preferably in the context of a net base-yielding diet, since a net acid-yielding diet increases excretion of both magnesium and calcium (table 2).

Table 2

Magnesium dietary sources

Potassium/sodium ratio affects calcium metabolism

A potassium/sodium ratio of 1.0 or higher is associated with a 50% lower risk of CVD and total mortality compared with a ratio under 1.0.35 Reducing excessive sodium intake is also associated with resultant decreased urinary calcium excretion, which may help to prevent against bone demineralisation.36 The average potassium content (about 2600 mg/day) of the typical US diet is substantially lower than its sodium content (about 3300 mg/day).35 Approximately 77% of dietary sodium chloride is consumed in the form of processed foods. By contrast, potassium is naturally abundant in many unprocessed foods, especially vegetables, fruits, tubers, nuts, legumes, fish and seafood. In fact, a high potassium/sodium ratio is a reliable marker for high intake of plant foods and lower intake of processed foods.35 High dietary sodium intake has been associated with endothelial damage, arterial stiffness, decreased nitric oxide production and increased levels of transforming growth factor β; whereas, high potassium dietary intake can counteract these effects.35 36

Evidence indicates that the lowest CV event rates occur in the moderate sodium excretion and high potassium excretion groups.37 Thus, it appears that a moderate sodium diet (2800–3300 mg/day) in conjunction with a high potassium intake (>3000 mg/day) might confer the optimal CV benefits for the general population.37

Vit K and bone health

Emerging evidence suggests that Vit K may confer protective effects for both the skeletal and CV systems. Vit K operates in the context of other fat-soluble vitamins, such as A and D, all of which are involved in maintenance of serum calcium concentration, along with the manipulation of materials leading to bone morphogenesis and maintenance of bone tissue.38 Specifically, the oxidation of Vit K results in activation/carboxylation of matrix Gla protein (MGP) which is partially responsible for mineralising bone.39

Also, Vit K is required for the activation (γ-carboxylation) of osteocalcin; the inactivated form, or per cent of undercaboxylated-osteocalcin (%ucOC), has been found to be a sensitive indicator of Vit K nutrition status.38 In cross-sectional and prospective analyses, elevated %ucOC, which occurs when Vit K status is low, is a marker of increased risk for hip fracture in the elderly.38

Several large observational studies appear to support the benefits of Vit K on bone health.38 A meta-analysis concluded that while supplementation with phytonadione (Vit K1) improved bone health, Vit K2 was even more effective in this regard.40 This large and statistically rigorous meta-analysis concluded that high Vit K2 levels were associated with reduced vertebral fractures by approximately 60% (95% CI 0.25% to 0.65%), hip fractures by 77% (95% CI 0.12% to 0.47%), and all non-vertebral fractures by approximately 81% (95% CI 0.11% to 0.35%). Moreover, the benefit of Vit K on bone may not be due to its ability to increase BMD, but rather to its effects at increasing bone strength.41

Vit K benefits in CV health

Mounting evidence suggests vascular calcification whether in the coronary or peripheral arteries is a powerful predictor of CV morbidity and all-cause mortality.42 Prevention of vascular calcification is therefore important as an early intervention to potentially improve long-term CV prognosis.

A major calcification inhibitory factor, is a Vit K-dependent protein synthesised by vascular smooth muscle cells.42 Increased Vit K2 intake has been associated with decreased arterial calcium deposition and the ability to reverse vascular calcification in animal models. Vit K2 prevents pathological calcification in soft tissues via the carboxylation of protective MGP. The undercarboxylated (inactive) species of MGP is formed during inadequate Vit K status, or as a result of Vit K antagonists.42 Low Vit K status is associated with increased vascular calcifications, and can be improved by effective Vit K supplementation (table 3).4344 In two different randomised, double-blind controlled trials, supplemental Vit K has been shown to significantly delay both the development of coronary artery calcification and the deterioration of arterial elasticity.45 46

Table 3

Vitamin K1 dietary sources

Dietary Vit K exists as two major forms: phylloquinone (K1) and menaquinones (MK-n). K1, the predominant dietary form of Vit K, is abundant in dark-green leafy vegetables and seeds. The main dietary sources for MK-n in Western populations are fermented foods, especially natto, cheese and curds (mainly MK-8 and MK-9).47

Calcium supplementation and bone health

A recent large meta-analysis of 26 randomised controlled trials reported that calcium supplements lowered the risk of any fracture by a modest but statistically significant 11% (n=58 573; RR 0.89, 95% CI 0.81 to 0.96).48

Importantly, a low dietary calcium intake with or without calcium supplementation is also associated with higher CV morbidity and mortality rates.51

Figure 3

Relationship of daily calcium intake to risk of CV mortality during follow-up. Data were fully adjusted for confounding variables. The calcium intake for optimising CV longevity is about 1000 mg/day, with higher and lower calcium intakes associated

Elevated serum calcium concentrations are associated with carotid artery plaque thickness, arterial and aortic calcification, and incidence of MI.57 58 Transient elevations in serum calcium levels have been noted following ingestion of 500–1000 mg of calcium supplements.63 64 By contrast, calcium from dietary sources or bone (calcium hydroxyapatite) ingestion results in much smaller changes in circulating calcium levels.

A plant-rich, grain-free diet alters the acid–base status so as to be slightly alkaline, which is conducive for bone health. However, plants are relatively poor sources of calcium compared to animal sources such as dairy products and animal bones. We suspect that milk, though an excellent source of bioavailable calcium, has potential adverse health effects for some individuals. Additionally, 65% of the world’s population show some decrease in lactase activity during adulthood. Importantly, fermented dairy has been linked to favourable outcomes for bone health and mortality risk.

In a small placebo-controlled randomised trial, women who took 1000 mg of calcium in the form of hydroxyapatite in conjunction with oral Vit D showed a significant increase in bone thickness, whereas those who took 1000 mg of a standard calcium carbonate supplement did not (figure 4).

In theory, consuming calcium-rich foods such as bones, fermented dairy (eg, unsweetened yogurt, kefir, cheese), leafy greens, almonds, and chia seeds may be an effective strategy for improving both calcium intake and long-term health.

Hormone therapy for prostate cancer may pose a risk for black men

By Lateshia Beachum

Black men treated with hormone therapy for prostate cancer may have a higher risk of death than white men undergoing the same therapy, according to a new study. But the deaths aren’t actually caused by prostate cancer.

Androgen deprivation therapy, or ADT, is a hormone treatment that shrinks prostate tumors. Researchers from the Brigham and Women’s Hospital in Boston found that black men undergoing the therapy had a 77 percent higher risk of death than non-black men.

Researchers at Brigham and Women’s Hospital looked through medical records of about 1,500 men from the Chicago Prostate Cancer Center with low- or intermediate-risk prostate cancer who were treated with ADT. About 7 percent were black.

The small study, in the journal Cancer, found that black men were usually younger, treated later and more likely to have other health issues.

Black men had a higher incidence of death after only four months of hormone therapy, the researchers found, but none of the causes of death in the study were actually prostate cancer.

Konstantin Kovtun, one of the lead researchers for the study, said the deaths seem to be related to cardiovascular health issues that existed prior to a cancer diagnosis. “African American men have an onset of cardiovascular problems that are linked to ADT use,” he said.

The study noted that earlier research has found shorter survival rates among intermediate- to high-risk prostate cancer patients using ADT because of an increased risk in fatal heart attack.

Jonathan Simons, president and chief executive officer of the Prostate Cancer Foundation, said the study was interesting but needs to be followed by more research, including a closer examination of the causes of death. “We don’t know the real reason for the number of deaths,” he said.

Black men typically fare worse with prostate cancer than white men, Simons said, and the reasons for the differences are understudied and poorly understood.

“You can have a man of European and a man of African descent,” he said. “Even if they get the same health care, insurance and doctors, black men still have it worse with prostate cancer.”

Kovtun hopes that the study helps inform decisions about treatment.

“If I was a physician and I had the data now available for the study, I would be more careful in using ADT for African American men,” he said.

 

Parsley, Natto, green tea and kiwi clean clogged arteries

PQQ can clean your clogged arteries.

pQQ PARSELY kiwi green tea green pepper papaya tofu

PQQ has been found in all plant foods analyzed to date. PQQ-rich foods include parsley, green peppers, kiwi fruit, papaya, fermented soybeans (Natto) and tofu. These foods contain about 2-3 mcg per 100 grams. Green tea provides about the same amount per 4 oz serving.

Pyrroloquinoline quinone (PQQ) has been reported as a promising agent that might contribute to tumor cell apoptosis and death, yet little is known on its mechanisms. In current study, the effect of PQQ on cell proliferation and mitochondrial-dependent apoptosis were examined in 3 solid tumor cell lines (A549, Neuro-2A and HCC-LM3). PQQ treatment at low to medium dosage exhibited potent anti-tumor activity on A549 and Neuro-2A cells, while had comparably minimal impact on the viabilities of 2 human normal cell lines (HRPTEpiC and HUVEC).

The apoptosis of the 3 tumor cell lines induced by PQQ were increased in a concentration-dependent manner, which might be attributed to the accumulation of intracellular reactive oxygen species (ROS), decline in ATP levels and dissipation of mitochondrial membrane potential (MMP), in conjunction with down-regulation of Bcl-2 protein expression, up-regulation of activated caspase-3, and disturbed phosphorylated MAPK protein levels. PQQ induced tumor cells apoptosis was significantly alleviated by pan-caspase inhibitor Z-VAD-FMK. The present work highlights the potential capability of PQQ as an anti-tumor agent with low toxicity towards normal cells through activating mitochondrial-dependent apoptosis pathways, and warrants its development for cancer therapy.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143536/

Pyrroloquinoline Quinone Resists Denervation-Induced Skeletal Muscle Atrophy by Activating PGC-1α and Integrating Mitochondrial Electron Transport Chain Complexes

Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression.