Magnesium, inflammation, and obesity in chronic disease.

About 60% of adults in the United States do not consume the estimated average requirement for magnesium, but widespread pathological conditions attributed to magnesium deficiency have not been reported. Nevertheless, low magnesium status has been associated with numerous pathological conditions characterized as having a chronic inflammatory stress component. In humans, deficient magnesium intakes are mostly marginal to moderate (approximately 50% to <100% of the recommended dietary allowance). Animal experiments indicate that signs of marginal-to-moderate magnesium deficiency can be compensated or exacerbated by other factors influencing inflammatory and oxidative stress; recent studies suggest a similar happening in humans. This suggestion may have significance in obesity, which is characterized as having a chronic low-grade inflammation component and an increased incidence of a low magnesium status. Marginal-to-moderate magnesium deficiency through exacerbating chronic inflammatory stress may be contributing significantly to the occurrence of chronic diseases such as atherosclerosis, hypertension, osteoporosis, diabetes mellitus, and cancer.

Nutr Rev. 2010 Jun;68(6):333-40

Magnesium metabolism and its disorders.

Magnesium is the fourth most abundant cation in the body and plays an important physiological role in many of its functions. Magnesium balance is maintained by renal regulation of magnesium reabsorption. The exact mechanism of the renal regulation is not fully understood. Magnesium deficiency is a common problem in hospital patients, with a prevalence of about 10%. There are no readily available and easy methods to assess magnesium status. Serum magnesium and the magnesium tolerance test are the most widely used. Measurement of ionised magnesium may become more widely available with the availability of ion selective electrodes. Magnesium deficiency and hypomagnesaemia can result from a variety of causes including gastrointestinal and renal losses. Magnesium deficiency can cause a wide variety of features including hypocalcaemia, hypokalaemia and cardiac and neurological manifestations. Chronic low magnesium state has been associated with a number of chronic diseases including diabetes, hypertension, coronary heart disease, and osteoporosis. The use of magnesium as a therapeutic agent in asthma, myocardial infarction, and pre-eclampsia is also discussed. Hypermagnesaemia is less frequent than hypomagnesaemia and results from failure of excretion or increased intake. Hypermagnesaemia can lead to hypotension and other cardiovascular effects as well as neuromuscular manifestations. Causes and management of hypermagnesaemia are discussed.

Clin Biochem Rev. 2003 May;24(2):47-66

Effects of magnesium depletion on inflammation in chronic disease.

PURPOSE OF REVIEW: To update findings supporting the opinion that commonly occurring subclinical magnesium deficiency induced by a low dietary intake is a predisposing factor for chronic inflammatory stress that contributes to the incidence of chronic diseases such as cardiovascular disease and diabetes. RECENT FINDINGS: Both deficient magnesium intakes (<250 mg/day) and serum magnesium concentrations (≤ 0.75 mmol/l) have been associated with elevated serum C-reactive protein concentration, a widely used indicator of inflammation. Achieving magnesium intakes or serum magnesium concentrations that indicate an adequate magnesium status generally attenuates elevated serum C-reactive protein to concentrations that are not indicative of chronic low-grade inflammation. Individuals that are obese or have chronic diseases for which low-grade inflammation is a risk factor are commonly found to be magnesium-deficient. SUMMARY: Subclinical magnesium deficiency caused by low dietary intake often occurring in the population is a predisposing factor for chronic inflammatory stress that is conducive for chronic disease. Magnesium deficiency should be considered a nutrient of significant concern for health and well-being.

Curr Opin Clin Nutr Metab Care. 2014 Nov;17(6):525-30

Role of magnesium in the pathogenesis and treatment of migraine.

Magnesium is an important intracellular element that is involved in numerous cellular functions. Deficiencies in magnesium may play an important role in the pathogenesis of migraine headaches by promoting cortical spreading depression, alteration of neurotransmitter release and the hyperaggregation of platelets. Given this multifaceted role of magnesium in migraine, the use of magnesium in both acute and preventive headache treatment has been researched as a potentially simple, inexpensive, safe and well-tolerated option. Studies have shown that preventive treatment with oral magnesium and acute headache treatment with intravenous magnesium may be effective, particularly in certain subsets of patients. In this review, the pathogenesis of migraine will be discussed, with an emphasis on the role of magnesium. Studies on the use of intravenous and oral magnesium in migraine treatment will be discussed and recommendations will be made regarding the use of magnesium in treating migraine headaches.

Expert Rev Neurother. 2009 Mar;9(3):369-79

Why all migraine patients should be treated with magnesium.

Magnesium, the second most abundant intracellular cation, is essential in many intracellular processes and appears to play an important role in migraine pathogenesis. Routine blood tests do not reflect true body magnesium stores since <2% is in the measurable, extracellular space, 67% is in the bone and 31% is located intracellularly. Lack of magnesium may promote cortical spreading depression, hyperaggregation of platelets, affect serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters. Migraine sufferers may develop magnesium deficiency due to genetic inability to absorb magnesium, inherited renal magnesium wasting, excretion of excessive amounts of magnesium due to stress, low nutritional intake, and several other reasons. There is strong evidence that magnesium deficiency is much more prevalent in migraine sufferers than in healthy controls. Double-blind, placebo-controlled trials have produced mixed results, most likely because both magnesium deficient and non-deficient patients were included in these trials. This is akin to giving cyanocobalamine in a blinded fashion to a group of people with peripheral neuropathy without regard to their cyanocobalamine levels. Both oral and intravenous magnesium are widely available, extremely safe, very inexpensive and for patients who are magnesium deficient can be highly effective. Considering these features of magnesium, the fact that magnesium deficiency may be present in up to half of migraine patients, and that routine blood tests are not indicative of magnesium status, empiric treatment with at least oral magnesium is warranted in all migraine sufferers.

J Neural Transm (Vienna). 2012 May;119(5):575-9

Relation between serum magnesium level and migraine attacks.

OBJECTIVE: The determination of serum magnesium levels in migraine. METHODS: In a case control study performed between January 2007 and December 2007 at Tabriz University of Medical Sciences, Tabriz, Iran, 140 migraine patients were enrolled and their level of serum magnesium was determined and the results were compared with 140 healthy people who did not have any headache, kidney, or gastrointestinal disorders, and no consumption of magnesium complements. RESULTS: Migraine patients (22 male, 118 female) with a mean age of 33.82+/-10.31 and 140 healthy people (26 male, 114 female) with a mean age of (34.19+/-9.95) were enrolled. Forty patients had aura and 100 patients did not have aura. The average serum magnesium level in the patient group (26.14+/-4.3) was significantly lower than the control (31.09+/-4.32) group (p=0.000). There was no significant difference between the mean level of serum magnesium in patients with migraine with aura and without aura, however, there was a significant linear relationship between the amount of serum magnesium and the frequency of headache. CONCLUSION: Serum magnesium in migraine patients was significantly lower than the normal population and related to the frequency of migraine attacks, supporting the use of magnesium in prevention and treatment of migraine.

Neurosciences (Riyadh). 2011 Oct;16(4):320-3

Magnesium and osteoporosis: current state of knowledge and future research directions.

A tight control of magnesium homeostasis seems to be crucial for bone health. On the basis of experimental and epidemiological studies, both low and high magnesium have harmful effects on the bones. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting on the secretion and the activity of parathyroid hormone and by promoting low grade inflammation. Less is known about the mechanisms responsible for the mineralization defects observed when magnesium is elevated. Overall, controlling and maintaining magnesium homeostasis represents a helpful intervention to maintain bone integrity.

Nutrients. 2013 Jul 31;5(8):3022-33

Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies.

BACKGROUND: Prospective studies of dietary magnesium intake in relation to risk of stroke have yielded inconsistent results. OBJECTIVE: We conducted a dose-response meta-analysis to summarize the evidence regarding the association between magnesium intake and stroke risk. DESIGN: Relevant studies were identified by searching PubMed and EMBASE from January 1966 through September 2011 and reviewing reference lists of retrieved articles. We included prospective studies that reported RRs with 95% CIs of stroke for ≥3 categories of magnesium intake. Results from individual studies were combined by using a random-effects model. RESULTS: Seven prospective studies, with 6,477 cases of stroke and 241,378 participants, were eligible for inclusion in the meta-analysis. We observed a modest but statistically significant inverse association between magnesium intake and risk of stroke. An intake increment of 100 mg Mg/d was associated with an 8% reduction in risk of total stroke (combined RR: 0.92; 95% CI: 0.88, 0.97), without heterogeneity among studies (P = 0.66, I(2) = 0%). Magnesium intake was inversely associated with risk of ischemic stroke (RR: 0.91; 95% CI: 0.87, 0.96) but not intracerebral hemorrhage (RR: 0.96; 95% CI: 0.84, 1.10) or subarachnoid hemorrhage (RR: 1.01; 95% CI: 0.90, 1.14). CONCLUSION: Dietary magnesium intake is inversely associated with risk of stroke, specifically ischemic stroke.

Am J Clin Nutr. 2012 Feb;95(2):362-6

Serum magnesium in patients with acute ischemic stroke.

Magnesium (Mg) has important effects within the vascular system. Magnesium deficiency was shown to trigger vasoconstriction and enhance vascular endothelial injury, thus promoting the development and progression of atherosclerosis. However, it is still not completely understood whether low serum Mg also promotes the occurrence of stroke. We hereby intended to investigate Mg levels in serum in the early stage of ischemic stroke and to evaluate the relationship between serum Mg concentration and the development of neurological deficits. The study included forty patients with acute ischemic stroke (26 women and 14 men), mean age 56 +/- 4 years, without any other serious injuries. Twenty-one healthy subjects, sex- and age-matched were selected as controls. The serum Mg concentrations were measured colorimetrically on a Hitachi 917 autoanalyzer. Serum levels of Mg were checked on admission, and at 48 hours after the onset of ischemic stroke. Using NIHSS, the neurological deficit was assessed on the 1st day, and 48 hours later. Statistical analysis was performed using the Student t test. The results confirm that there is a relationship between a low Mg concentration in serum at 48 hours after onset of ischemic stroke and the intensity of the neurological deficit. Mean value was 1.39 +/- 0.213 mmol/L (on admission), 1.47 +/- 0.181 mmol/L (at 48 hours after the onset of stroke) versus 1.66 +/- 0.138 mmol/L (in controls). Severity of paresis degree was higher in the patients with low Mg levels (p < 0.05). The serum Mg concentration has been suggested to possibly affect the neurologic state. A decrease in the serum Mg concentration indicates the severity of the injury. A magnesium substitution therapy may be useful.

Rom J Intern Med. 2007;45(3):269-73

Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies.

BACKGROUND: Clinical hypomagnesemia and experimental restriction of dietary magnesium increase cardiac arrhythmias. However, whether or not circulating or dietary magnesium at usual concentrations or intakes influences the risk of cardiovascular disease (CVD), including fatal ischemic heart disease (IHD), is unclear. OBJECTIVE: We performed a systematic review and meta-analysis to investigate prospective associations of circulating and dietary magnesium with incidence of CVD, IHD, and fatal IHD. DESIGN: Multiple literature databases were systematically searched without language restriction through May 2012. Inclusion decisions and data extraction were performed in duplicate. Linear dose-response associations were assessed by using random-effects meta-regression. Potential nonlinear associations were evaluated by using restricted cubic splines. RESULTS: Of 2,303 articles, 16 studies met the eligibility criteria; these studies comprised 313,041 individuals and 11,995 CVD, 7,534 IHD, and 2,686 fatal IHD events. Circulating magnesium (per 0.2 mmol/L increment) was associated with a 30% lower risk of CVD (RR: 0.70; 95% CI: 0.56, 0.88 per 0.2 mmol/L) and trends toward lower risks of IHD (RR: 0.83; 95% CI: 0.75, 1.05) and fatal IHD (RR: 0.61; 95% CI: 0.37, 1.00). Dietary magnesium (per 200-mg/d increment) was not significantly associated with CVD (RR: 0.89; 95% CI: 0.75, 1.05) but was associated with a 22% lower risk of IHD (RR: 0.78; 95% CI: 0.67, 0.92). The association of dietary magnesium with fatal IHD was nonlinear (P < 0.001), with an inverse association observed up to a threshold of ~250 mg/d (RR: 0.73; 95% CI: 0.62, 0.86), compared with lower intakes. CONCLUSION: Circulating and dietary magnesium are inversely associated with CVD risk, which supports the need for clinical trials to evaluate the potential role of magnesium in the prevention of CVD and IHD.

Am J Clin Nutr. 2013 Jul;98(1):160-73

High serum uric acid level in adolescent depressive patients.

BACKGROUND: Depression disorder is a mental illness of high recurrence rate and its pathological mechanism is still unclear. 5-HT is the most widely studied neurotransmitter and high level of serum uric acid (SUA) can result from the increased oxygenolysis of nucleic acid. Aim of the present study is to explore the pathogenesis of adolescence depression through the study of SUA and 5-HT level in adolescent depressive patients. METHODS: The SUA of 152 adolescent depressive patients and normal adolescents were tested respectively and 5-HT levels among them were analyzed.RESULTS: The SUA level of cases (434.57±102.34µmol/L) was significantly higher than controls (330.18±62.59µmol/L), P<0.001; the 5-HT level of cases (20.86±4.58) was significantly lower than controls (24.03±5.76) (P<0.005) and had a significant negative correlation with SUA level (r=-0.49, P<0.01). LIMITATIONS: The sample size was relatively small and the patients were only male from General Hospital of Beijing Military Region. CONCLUSIONS: High level of SUA can be used as a biochemical index for the early diagnose of adolescence depression; adolescence depression may be due to DNA oxidative damage of neurons in brain.

J Affect Disord. 2015 Mar 15;174:464-6

Impact of Serum Uric Acid Levels on Coronary Plaque Stability Evaluated Using Integrated Backscatter Intravascular Ultrasound in Patients with Coronary Artery Disease.

AIM: Because the prevalence of hyperuricemia is lower in females than in males, the association between hyperuricemia and cardiovascular disease has been frequently reported in females. Increased serum uric acid levels are associated with the presence of cardiovascular risk factors such as hypertension, renal dysfunction, insulin resistance, and metabolic syndrome. However, it is controversial whether hyperuricemia is an independent risk factor for coronary artery disease in both the genders. The purpose of this study was to investigate the relationship between serum uric acid levels and coronary plaque components assessed using integrated backscatter intravascular ultrasound (IB-IVUS) in males and females. METHODS: In total, 385 patients (298 males and 87 females) who underwent percutaneous coronary intervention using IB-IVUS were divided into three groups in each gender according to their serum uric acid levels. We characterized tissue from coronary plaques in culprit lesions. RESULTS: Serum uric acid levels significantly correlated with percent lipid volume (r=0.37) and inversely correlated with percent fibrous volume (r=－0.35). Multivariate analysis showed that the uric acid level was independently associated with lipid-rich plaques (odds ratio 2.43, 95%, confidence interval 1.75-3.47). The prevalence of lipid-rich plaques increased with increasing uric acid levels in both genders. CONCLUSION: Increased serum uric acid levels were associated with larger lipid content plaques in both genders.

J Atheroscler Thromb. 2016 Aug 1;23(8):932-9

Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is mediated by oxidative stress, neurohormonal activation, and inflammatory activation. Serum uric acid (SUA) is a surrogate marker of oxidative stress. Xanthine oxidase produces SUA and is upregulated by inflammation and neurohormones. OBJECTIVE: To perform a meta-analysis to evaluate the evidence supporting an association between AF and SUA. METHODS: We searched the MEDLINE database (1966 to 2013) supplemented by manual searches of bibliographies of key relevant articles. We selected all cross-sectional and cohort studies in which SUA was measured and AF was reported. In cross-sectional studies, we calculated the pooled standardized mean difference of SUA between those with AF and those without AF. In cohort studies, we calculated the pooled relative risk with the corresponding 95% confidence interval (CI) for incident AF by using the random effects method. RESULTS: The search strategy yielded 40 studies, of which only 9 met our eligibility criteria. The 6 cross-sectional studies comprised 7,930 evaluable patients with a median prevalence of heart failure of 4% (IQR 0%-100%). The standardized mean difference of SUA for those with AF was 0.42 (95% CI 0.27-0.58) compared with those without AF. The 3 cohort studies evaluated 138,306 individuals without AF. The relative risk of having AF for those with high SUA was 1.67 (95% CI 1.23-2.27) compared with those with normal SUA. CONCLUSION: High SUA is associated with AF in both cross-sectional and cohort studies. It is unclear whether SUA represents a disease marker or a treatment target.

Heart Rhythm. 2014 Jul;11(7):1102-8

Serum Uric Acid and Prehypertension Among Adults Free of Cardiovascular Diseases and Diabetes: Baseline of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

The association between serum uric acid (SUA) and prehypertension was evaluated in a racially admixed sample of civil servants aged 35 to 74 years, enrolled (2008-2010) in the Brazilian Longitudinal Study of Health (ELSA-Brasil). Of the 15,105 patients who enrolled in the study, we analyzed 3,412 after excluding those who reported previous cardiovascular diseases, diabetes, or hypertension; were heavy drinkers; or had a body mass index (BMI) ≥ 35 kg/m(2). Among the men, logistic regression, adjusted for age, race, income, birth weight, salt intake, insulin resistance, BMI, and renal function revealed odds ratios (ORs) and 95% confidence intervals (CIs) of prehypertension from the bottom quartile (referent) to the top quartile of SUA levels as follows: 0.84 (95% CI, 0.61-1.38), 0.97 (0.71-1.34) and 1.44 (1.04-2.0; P for trend .01). Analyzing for 1-standard deviation of change in SUA, the ORs were 1.19 (1.06-1.32). This association persisted in the subgroup analysis consisting of patients who were white, overweight, with a high salt intake but with normal renal function, and without metabolic syndrome. No association was found among women. In conclusion, SUA levels were associated with prehypertension among men.

Angiology. 2016 Feb;67(2):180-6

Gender differences in the association between serum uric acid and prognosis in patients with acute coronary syndrome.

BACKGROUND: Increased levels of uric acid (UA) have been associated with cardiovascular disease. This association is generally stronger in women than men. However, gender differences in the prognostic value of UA in patients with acute coronary syndrome (ACS) are unknown. We investigated gender differences in the relationship between UA level and the prognosis in patients with ACS. METHOD: This was an observational analysis of patients with ACS undergoing percutaneous coronary intervention enrolled in the Ibaraki Cardiac Assessment Study (ICAS) registry. We analyzed 1,380 patients (330 women, 1050 men) with ACS who had information on UA. We assessed the association between UA and the incidence of major cardiovascular adverse events (MACE), defined as all-cause death, congestive heart failure, reinfarction, and stroke. Patients were divided according to gender-specific UA quartile. RESULTS: The mean UA level in women was significantly lower than that in men (4.9mg/dl vs 5.9mg/dl, p<0.001). After a median duration of follow-up period of 437 days (interquartile range 222-801 days), MACE had occurred in 186 (13%) patients [56 (17%) events in women; 130 (12%) events in men]. Kaplan-Meier analysis for MACE-free survival demonstrated that a higher quartile of UA was associated with MACE in both women and men (p<0.001, p=0.002, respectively). Multivariate Cox regression analysis revealed that the highest quartile of UA, as compared with the lowest quartile of UA, was an independent predictor of MACE in women [hazard ratio (HR), 2.84; 95% CI, 1.19-6.77; p=0.018] but not in men (HR, 1.32; 95% CI, 0.66-2.64; p=0.422). CONCLUSIONS: An increased level of UA was associated with MACE more strongly in women than in men with ACS. These results suggest that there are gender differences in the association of UA level with the prognosis in patients with ACS.

J Cardiol. 2016 Feb;67(2):170-6

The association between serum uric acid level and heart failure and mortality in the early period of ST-elevation acute myocardial infarction.

OBJECTIVES: Uric acid (UA) is a strong marker of cardiovascular disease. Therefore, we aimed to determine the relationship between serum UA levels and cardiovascular events in patients in the early period of their acute myocardial infarction. STUDY DESIGN: This retrospective study included 586 consecutive patients with ST-elevated myocardial infarction (STEMI) who were admitted to the hospital between March 2010 and February 2012. The study population was divided into two groups; the first group included hyperuricemic patients (n=107; uric acid level >6 mg/dl in women and >7 mg/dl in men), and the second group included patients with normal UA level (n=479). Multivariate analysis was used to demonstrate the predictive value of UA levels in groups. RESULTS: Patients in the hyperuricemic group were older (median 66 years vs. 60 years, p=0.001), and the ratio of female patients was higher (35.5% vs. 16.9%, p=0.001). Patients with hyperuricemia had a significantly higher incidence of in-hospital cardiovascular mortality than the normal group (15.9% vs. 3.1%, p<0.001). Advanced heart failure (class ≥ 3) was more frequent among hyperuricemic patients (17.8% vs. 8.8%, p=0.006). Age ≥ 70 years, chest pain duration >6 hours and hyperuricemia (hazard ratio (HR): 1.83, 95% confidence interval: 1.02-3.27; p=0.041) were found to be independent predictors of advanced heart failure. Hyperuricemia was found to be an independent predictor of in-hospital cardiovascular mortality in multivariate analyses (HR: 5.32, 95% confidence interval: 2.46-11.49; p=0.001). CONCLUSION: This study showed that a high serum UA level is an independent predictor of cardiovascular mortality and morbidity during the in-hospital period of STEMI.

Turk Kardiyol Dern Ars. 2014 Sep;42(6):501-8

Uric Acid and New Onset Left Ventricular Hypertrophy: Findings From the PAMELA Population.

BACKGROUND: The association between serum uric acid (SUA) and left ventricular hypertrophy (LVH) is controversial and the ability of SUA in predicting incident LVH remains unsettled. Thus, we evaluated the relationship of SUA with new-onset echocardiographic LVH over a 10-year period in subjects of the general population enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study. METHODS: The study included 960 subjects with normal LV mass index (LVMI) at baseline echocardiographic evaluation and a readable echocardiogram at the end of follow-up. Cut-points for LVH were derived from reference values of the healthy fraction of the PAMELA population. RESULTS: Over a 10-year period, 258 participants (26.9%) progressed to LVH. The incidence of new-onset LVH increased from the lowest (23%) to intermediate (25%) and the highest baseline SUA tertile (32%). After adjusting for confounders (not including body mass index (BMI)), each 1 mg/dl increase in SUA entailed a 26% higher risk of incident LVH. Adjusted odd ratio of LVH risk in the highest SUA tertile was 96% higher than in the lowest tertile (odds ratio (OR) = 1.966, 95% CI = 1.158-3.339, P = 0.0123). Correction for BMI reduced the magnitude and statistical significance of ORs. CONCLUSIONS: The study shows that SUA is a predictor of long-term echocardiographic changes from normal LVMI to LVH in a community sample. Thus, life-style and pharmacologic measures aimed to reduce SUA levels may concur to preventing LVH development in the general population.

Am J Hypertens. 2017 Mar 1;30(3):279-285

Green tea and the prevention of breast cancer: a case-control study in Southeast China.

Breast cancer is the most common malignancy in women worldwide. Tea has anticarcinogenic effects against breast cancer in experimental studies. However, epidemiologic evidence that tea protects against breast cancer has been inconsistent. A case-control study was conducted in Southeast China between 2004 and 2005. The incidence cases were 1,009 female patients aged 20-87 years with histologically confirmed breast cancer. The 1,009 age-matched controls were healthy women randomly recruited from breast disease clinics. Information on duration, frequency, quantity, preparation, type of tea consumption, diet and lifestyle were collected by face-to-face interview using a validated and reliable questionnaire. Conditional logistic regression analyses were used to estimate odds ratios (ORs) and associated 95% confidence intervals. Compared with non-tea drinkers, green tea drinkers tended to reside in urban, have better education and have higher consumption of coffee, alcohol, soy, vegetables and fruits. After adjusting established and potential confounders, green tea consumption was associated with a reduced risk of breast cancer. The ORs were 0.87 (0.73-1.04) in women consuming 1-249 g of dried green tea leaves per annum, 0.68 (0.54-0.86) for 250-499 g per annum, 0.59 (0.45-0.77) for 500-749 g per annum and 0.61 (0.48-0.78) for >or=750 g per annum, with a statistically significant test for trend (P < 0.001). Similar dose-response relationships were observed for duration of drinking green tea, number of cups consumed and new batches prepared per day. We conclude that regular consumption of green tea can protect against breast cancer. More research to closely examine the relationship between tea consumption and breast cancer risk is warranted.

Carcinogenesis. 2007 May;28(5):1074-8

Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan.

Experimental studies suggest various features of anticancer activity of green tea including inhibitory effect of tumor invasion and metastasis. This study was conducted to examine the association between regular green tea consumption prior to diagnosis and subsequent risk of breast cancer recurrence. The Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) was started in 1988, in which information on lifestyle has routinely been collected from all first-visit outpatients by questionnaire. A total of 1160 new surgical cases of female invasive breast cancers with HERPACC information diagnosed between June 1990 and August 1998 were followed up through December 1999, and the risk (hazard ratio: HR) of recurrence was assessed with reference to daily green tea consumption using a Cox proportional hazard model. During 5,264 person-years of follow-up, 133 subjects (12%) were documented to suffer recurrence of breast cancer. A decreased HR for recurrence adjusted for stage was observed with consumption of three or more daily cups of green tea (HR=0.69, 95% confidence interval (95%CI)=0.47-1.00). Particularly in stage I, the HR was decreased statistically significantly (HR=0.43, 95%CI=0.22-0.84). A similar tendency was observed for stage II subjects, but was not present among more advanced stages. Although careful interpretation is needed, these results suggest the possibility that regular green tea consumption may be preventive against recurrence of breast cancer in early stage cases.

Cancer Lett. 2001 Jun 26;167(2):175-82

Modulation of MMP-2 and MMP-9 secretion by cytokines, inducers and inhibitors in human glioblastoma T-98G cells.

Brain tumors are highly aggressive, characterized by the secretion of high levels of matrix metalloproteinase (MMP)-2 and MMP-9 that degrade the extracellular matrix and basement membrane, allowing cancer cells to spread to distal organs. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activity. We investigated the roles of these in the regulation of MMP-2 and MMP-9 in human glioblastoma T-98G cells. Human T-98G cells were grown in DME supplemented with 15% fetal bovine serum and antibiotics in 24-well tissue culture plates. At near confluence, cells were washed with phosphate-buffered saline and incubated in serum-free media with: phorbol 12-myristate 13-acetate (PMA) at 10, 25, 50 and 100 ng/ml; tumor necrosis factor (TNF)-a and interleukin (IL)-1b at 0.1, 1, 10 and 25 ng/ml; lipopolysaccharide (LPS) at 10, 25, 50 and 100 µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10, 25, 50 and 100 µM without and with PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract without and with PMA at 10, 50, 100, 500 and 1,000 µg/ml; actinomycin D and cyclohexamide at 2 and 4 µM; retinoic acid and dexamethasone at 50 µM. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by zymography and densitometry. Glioblastoma T-98G cells expressed only one band corresponding to MMP-2. PMA treatment showed increased MMP-2 and MMP-9 secretions up to 25 ng/ml and decreased levels of secretions at 50 and 100 ng/ml, with no significant overall effect. TNF-a induced an up and down effect on MMP-2 and a slight induction of MMP-9. IL-1b demonstrated a slight dose-dependent increase in T-98G secretion of MMP-2, but no induction of MMP-9. LPS showed dose-dependent decreased inactive MMP-2 secretion, increased active MMP-2 secretion and no effect on MMP-9. EGCG, Dox and NM, without and with PMA, downregulated the expression of MMP-2 and MMP-9 in a dose-dependent manner. Actinomycin D, cyclohexamide, retinoic acid and dexamethasone also had inhibitory effects on MMP-2. Our results showed that cytokines, mitogens and inhibitors modulated T-98G cell MMP-2 and MMP-9 expression, suggesting the clinical use of MMP inhibitors, particularly such potent and non-toxic ones as the nutrient mixture and its component EGCG in the management of glioblastoma cancers.

Oncol Rep. 2017 Mar;37(3):1907-1913

Green Tea Polyphenol Induces Changes in Cancer-Related Factors in an Animal Model of Bladder Cancer.

Green tea polyphenol (GTP) suppresses carcinogenesis and aggressiveness in many types of malignancies including bladder cancer. However, the mechanistic basis of these effects is not well understood. This was investigated in the present study using a mouse model of chemically induced bladder cancer. C3H/He mice (8 weeks old; n = 46) were treated with 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) solution for 14-24 weeks. Mice in the BBN + GTP group (n = 47) were also treated with 0.5% GTP solution over the same period. Tumor cell proliferation and microvessel density were evaluated along with immunohistochemical analysis of human antigen (Hu)R, vascular endothelial growth factor (VEGF)-A, cyclooxygenase (COX)-2, and hemeoxygenase (HO)-1 expression. Cytoplasmic HuR expression in cancer cells was higher at 14 and 24 weeks in the BBN than in the control group and was associated with increased invasion of tumor cells in muscle. However, these effects were not observed in the BBN + GTP group. A multivariate analysis of GTP intake and cytoplasmic HuR expression revealed that GTP was independently associated with COX-2 and HO-1 expression, while cytoplasmic HuR expression was associated with COX-2 and VEGF-A levels. Expression of COX-2 and HO-1 was associated with cell proliferation and that of VEGF-A and HO-1 was associated with angiogenesis. Nuclear HuR expression was not associated with any parameters such as carcinogenesis, muscle invasion, and GTP intake. These results indicate that GTP intake can suppress tumor progression and malignant behavior in an animal model of bladder cancer. We also speculate that GTP directly and indirectly suppresses tumor cell proliferation and angiogenesis via HuR-related pathways in bladder cancer.

PLoS One. 2017 Jan 31;12(1):e0171091

Preparation of catechin extracts and nanoemulsions from green tea leaf waste and their inhibition effect on prostate cancer cell PC-3.

Green tea is one of the most commonly consumed natural health beverages in Taiwan’s market, with the major functional component catechin being shown to possess several biological activities such as antioxidation, anticancer, and prevention of cardiovascular disease. The objectives of this study were to develop a high-performance liquid chromatography-mass spectrometry method to determine the variety and content of catechins in green tea leaf waste, a by-product obtained during processing of tea beverage. In addition, catechin nanoemulsion was prepared to study its inhibition effect on prostate cancer cell PC-3. Results showed that a total of eight catechin standards were separated within 25 minutes by using a Gemini C18 column and a gradient mobile phase of 0.1% formic acid (A) and acetonitrile (B) with flow rate at 1 mL/min, column temperature at 30°C, and detection wavelength at 280 nm. Among various extraction solvents, 50% ethanol generated the highest yield of total catechins from tea leaf waste, of which five catechins were identified and quantified. The catechin nanoemulsion was composed of catechin extract, lecithin, Tween 80, and deionized water in an appropriate proportion, with the mean particle size being 11.45 nm, encapsulation efficiency 88.1%, and zeta potential -66.3 mV. A high stability of catechin nanoemulsion was shown over a storage period of 120 days at 4°C. Both catechin extract and nanoemulsion could inhibit growth of PC-3 tumor cells, with the half maximal inhibitory concentration being 15.4 µg/mL and 8.5 µg/mL, respectively. The PC-3 cell cycle was arrested at S phase through elevation of P27 expression and decline of cyclin A, cyclin B, cyclin-dependent kinase 2, and cyclin-dependent kinase 1 expression. In addition, both catechin extract and nanoemulsion could induce apoptosis of PC-3 cells through decrease in B-cell lymphoma 2 (bcl-2) expression and increase in cytochrome c expression for activation of caspase-3, caspase-8, and caspase-9. Taken together, both caspase-dependent and caspase-independent pathways may be involved in apoptosis of PC-3 cells.

Int J Nanomedicine. 2016 May 6;11:1907-26

Epigallocatechin-3-O-gallate up-regulates microRNA-let-7b expression by activating 67-kDa laminin receptor signaling in melanoma cells.

MicroRNAs (miRNAs) are non-coding RNAs involved in various biological processes by regulating their target genes. Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) inhibits melanoma tumor growth by activating 67-kDa laminin receptor (67LR) signaling. To examine the effect of EGCG on miRNA expression in melanoma cells, we performed miRNA microarray analysis. We showed that EGCG up-regulated miRNA-let-7b expression through 67LR in melanoma cells. The EGCG-induced up-regulation of let-7b led to down-regulation of high mobility group A2 (HMGA2), a target gene related to tumor progression. 67LR-dependent cAMP/protein kinase A (PKA)/protein phosphatase 2A (PP2A) signaling pathway activation was involved in the up-regulation of let-7b expression induced by EGCG. These findings provide a basis for understanding the mechanism of miRNA regulation by EGCG.

Sci Rep. 2016 Jan 12;6:19225

Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer’s amyloid-induced mitochondrial dysfunction.

Amyloid-b (Ab)-induced mitochondrial dysfunction may play a role in the onset and progression of Alzheimer’s disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Plant-derived flavonoids have shown promise in improving certain AD phenotypes, but the overall mechanism of action(s) through which flavonoids protect from AD is still unknown. To identify flavonoids and other natural products that may correct amyloid-induced mitochondrial dysfunction, 25 natural products were screened for their ability to restore altered mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, or ATP levels in neuroblastoma cells expressing mutant amyloid-b protein precursor (AbPP). Epigallocatechin-3-gallate (EGCG) and luteolin were identified as the top two mitochondrial restorative compounds from the in vitro screen. EGCG was further tested in vivo to determine its effects on brain mitochondrial function in an AbPP/PS-1 (presenilin 1) double mutant transgenic mouse model of AD. EGCG treatment restored mitochondrial respiratory rates, MMP, ROS production, and ATP levels by 50 to 85% in mitochondria isolated from the hippocampus, cortex, and striatum. The results of this study lend further credence to the notion that EGCG and other flavonoids, such as luteolin, are ‘multipotent therapeutic agents’ that not only reduce toxic levels of brain Ab, but also hold the potential to protect neuronal mitochondrial function in AD.

J Alzheimers Dis. 2011;26(3):507-21

Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people.

OBJECTIVE: To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption. METHODS: Sixty older people (aged 72.9 ± 5.4 years) were studied in a parallel-arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI-eligible participants, cerebral white matter structural integrity was also measured. RESULTS: Neurovascular coupling was associated with Trails B scores (p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities (p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% ± 7.2% vs -2.4% ± 4.8%; p = 0.001) and improved Trails B times (116 ± 78 seconds vs 167 ± 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline. CONCLUSION: There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity.

Neurology. 2013 Sep 3;81(10):904-9

Phenolic and Volatile Composition of a Dry Spearmint (Mentha spicata L.) Extract.

The present paper reports a complete mass spectrometric characterization of both the phenolic and volatile fractions of a dried spearmint extract. Phenolic compounds were analysed by ultra-high performance liquid chromatography-electrospray ionization-mass spectrometry (UHPLC-ESI-MS(n)) and a total of 66 compounds were tentatively identified, being the widest phenolic characterisation of spearmint to date. The analysis suggests that the extract is composed of rosmarinic acid and its derivatives (230.5 ± 13.5 mg/g) with smaller amounts of salvianolic acids, caffeoylquinic acids, hydroxybenzoic acids, hydroxycinnamic acids, flavones, and flavanones. Head space solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS) technique, that was applied to characterize the volatile fraction of spearmint, identified molecules belonging to different chemical classes, such as p-cymene, isopiperitone, and piperitone, dihydroedulan II, menthone, p-cymen-8-ol, and b-linalool. This comprehensive phytochemical analysis can be useful to test the authenticity of this product rich in rosmarinic acid and other phenolics, and when assessing its biological properties. It may also be applied to other plant-derived food extracts and beverages containing a broad range of phytochemical compounds.

Molecules. 2016 Aug 3;21(8). pii: E1007

Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study.

Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy- and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function.

Neuroimage. 2014 Jan 15;85 Pt 1:592-607

Neurovascular and neurometabolic derailment in aging and Alzheimer’s disease.

The functional and structural integrity of the brain requires local adjustment of blood flow and regulated delivery of metabolic substrates to meet the metabolic demands imposed by neuronal activation. This process-neurovascular coupling-and ensued alterations of glucose and oxygen metabolism-neurometabolic coupling-are accomplished by concerted communication between neural and vascular cells. Evidence suggests that neuronal-derived nitric oxide ((•)NO) is a key player in both phenomena. Alterations in the mechanisms underlying the intimate communication between neural cells and vessels ultimately lead to neuronal dysfunction. Both neurovascular and neurometabolic coupling are perturbed during brain aging and in age-related neuropathologies in close association with cognitive decline. However, despite decades of intense investigation, many aspects remain poorly understood, such as the impact of these alterations. In this review, we address neurovascular and neurometabolic derailment in aging and Alzheimer’s disease (AD), discussing its significance in connection with (•)NO-related pathways.

Front Aging Neurosci. 2015 May 27;7:103

Neurovascular coupling is impaired in cerebral microangiopathy—An event-related Stroop study.

Small-vessel disease or cerebral microangiopathy is a common finding in elderly people leading finally to subcortical ischemic vascular dementia. Because cerebral microangiopathy impairs vascular reactivity and affects mainly the frontal lobes, we hypothesized that brain activation decreases during an event-related color-word matching Stroop task. 12 patients suffering from cerebral microangiopathy were compared with 12 age-matched controls. As an imaging method we applied functional near-infrared spectroscopy, because it is particularly sensitive to the microvasculature. The Stroop task led to activations in the lateral prefrontal cortex. Generally, the amplitude of the hemodynamic response was reduced in patients in tight correlation with behavioral slowing during the Stroop task and with neuropsychological deficits, namely attentional and executive dysfunction. Interestingly, patients showed an early deoxygenation of blood right after stimulation onset, and a delay of the hemodynamic response. Whereas the amplitude of the hemodynamic response is reduced in the frontal lobes also with normal aging, data suggest that impairments of neurovascular coupling are specific for cerebral microangiopathy. In summary, our findings indicate frontal dysfunction and impairments of neurovascular coupling in cerebral microangiopathy.

Neuroimage. 2007 Jan 1;34(1):26-34

Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.

The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.

J Appl Physiol (1985). 2006 Jan;100(1):328-35

Preventive antioxidant effects of cocoa polyphenolic extract on free radical production and cognitive erformances after heat exposure in Wistar rats.

The preventive effects of ACTICOA powder (AP), a cocoa polyphenolic extract, on free radicals produced by leucocytes in rats after heat exposure (HE) and its protective effects on subsequent cognitive impairments were assessed. AP or vitamin E, the antioxidant reference, was orally administered to rats for 14 d before HE at 40 degrees C temperature during 2 h. The day after HE, free radical production by leucocytes in rats treated with AP or vitamin E was significantly reduced as compared to control. Unlike controls, AP- and vitamin E-treated rats discriminated between active lever and inactive levers in a light extinction paradigm. In the Morris water maze, escape latencies before reaching the hidden platform by AP- and vitamin E-treated rats decreased throughout testing. The daily oral administration of AP or vitamin E protected rats from cognitive impairments after HE by counteracting the overproduction of free radicals.

J Food Sci. 2007 Apr;72(3):S203-6

Effect of botanical extracts containing carnosic acid or rosmarinic acid on learning and memory in SAMP8 mice.

Oxidative damage is one of the hallmarks of the aging process. The current study evaluated effects of two proprietary antioxidant-based ingredients, rosemary extract and spearmint extract containing carnosic acid and rosmarinic acid, respectively, on learning and memory in the SAMP8 mouse model of accelerated aging. The two rosemary extracts contained carnosic acid (60% or 10% carnosic acid) and one spearmint extract contained 5% rosmarinic acid. Three doses of actives in each extract were tested: 32, 16, 1.6 or 0mg/kg. After 90days of treatment mice were tested in T-maze foot shock avoidance, object recognition and lever press. Rosemary extract containing 60% carnosic acid improved acquisition and retention in T-maze foot shock, object recognition and lever press. Rosemary extract with 10% carnosic acid improved retention in T-maze foot shock avoidance and lever press. Spearmint with 5% rosmarinic acid improved acquisition and retention in T-maze foot shock avoidance and object recognition. 4-hydroxynonenal (HNE) was reduced in the brain cortex after treatment with all three extracts (P<0.001) compared to the vehicle treated SAMP8. Protein carbonyls were reduced in the hippocampus after administration of rosemary with 10% carnosic acid (P<0.05) and spearmint containing 5% rosmarinic acid (P<0.001). The current results indicate that the extracts from spearmint and rosemary have beneficial effects on learning and memory and brain tissue markers of oxidation that occur with age in SAMP8 mice.

Physiol Behav. 2016 Oct 15;165:328-38