2012 The neuroprotective effects of cocoa flavanol and its influence on cognitive performance.

The neuroprotective effects of cocoa flavanol and its influence on cognitive performance.

flavonoids preserve cognitive abilities during ageing in rats, lower the risk for developing Alzheimer's disease and decrease the risk of stroke in humans.

Caffeine, Fluid-Electrolyte Balance, Temperature Regulation,... : Exercise and Sport Sciences Reviews

«Dietitians, exercise physiologists, athletic trainers, and other sports medicine personnel commonly recommend that exercising adults and athletes refrain from caffeine use because it is a diuretic, and it may exacerbate dehydration and hyperthermia. This review, contrary to popular beliefs, proposes that caffeine consumption does not result in the following: (a) water-electrolyte imbalances or hyperthermia and (b) reduced exercise-heat tolerance.»

1983 Inhibition of food iron absorption by coffee.

2009 The Effect of Daily Caffeine Use on Cerebral Blood Flow: How Much Caffeine Can We Tolerate?

"Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. We investigated the effects of caffeine on cerebral blood flow (CBF) in increasing levels of chronic caffeine use. Low (mean = 45 mg/day), moderate (mean = 405 mg/day), and high (mean = 950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. Our results suggest a limited ability of the cerebrovascular adenosine system to compensate for high amounts of daily caffeine use."

2012 Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects

«Significant reductions were observed in body weight (−8.04 ± 2.31 kg), body mass index (−2.92 ± 0.85 kg/m²), and percent body fat (−4.44% ± 2.00%), as well as a small decrease in heart rate (−2.56 ± 2.85 beats per minute), but with no significant changes to diet over the course of the study. Importantly, the decreases occurred when subjects were taking GCA. Body mass index for six subjects shifted from preobesity to the normal weight range (<25.00 kg/m²).»

2014 Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review

«Caffeine is the most consumed pychostimulant in the world, and it is known to affect basic and fundamental human processes such as sleep, arousal, cognition and learning and memory. It works as a nonselective blocker of adenosine receptors (A1, A2a, A2b and A3) and has been related to the regulation of heart rate, the contraction/relaxation of cardiac and smooth muscles, and the neural signaling in the central nervous system (CNS). Since the late 1990s, studies using adenosine receptor antagonists, such as Caffeine, to block the A1 and A2a adenosine receptor subtypes have shown to reduce the physical, cellular and molecular damages caused by a spinal cord injury (SCI) or a stroke (cerebral infarction) and by other neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Interestingly, other studies using adenosine receptor agonists have also shown to provide a neuroprotective effect on various models of neurodegenerative diseases through the reduction of excitatory neurotransmitter release, apoptosis and inflammatory responses, among others. The seemingly paradoxical use of both adenosine receptor agonists and antagonists as neuroprotective agents has been attributed to differences in dosage levels, drug delivery method, extracellular concentration of excitatory neurotransmitters and stage of disease progression. We discuss and compare recent findings using both antagonists and agonists of adenosine receptors in animal models and patients that have suffered spinal cord injuries, brain stroke, and Parkinson's and Alzheimer's diseases. Additionally, we propose alternative interpretations on the seemingly paradoxical use of these drugs as potential pharmacological tools to treat these various types of neurodegenerative diseases.»

2015 Role of Caffeine Intake on Erectile Dysfunction in US Men: Results from NHANES 2001-2004

«We found that men in the 3^rd (85-170 mg/day) and 4^th (171-303 mg/day) quintiles of caffeine intake were less likely to report ED compared to men in the lowest 1^st quintile (0-7 mg/day) [OR: 0.58; 95% CI, 0.37–0.89; and OR: 0.61; 95% CI, 0.38–0.97, respectively], but no evidence for a trend. Similarly, among overweight/obese and hypertensive men, there was an inverse association between higher quintiles of caffeine intake and ED compared to men in the lowest 1^st quintile, P≤0.05 for each quintile. However, only among men without diabetes we found a similar inverse association (P_trend = 0.01).»

2018 Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression

«Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy) and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemiological data suggest that caffeine consumption can have an impact on aspects of depressive symptomatology. Caffeine is a non-selective adenosine antagonist for A₁/A_2A receptors, and has been demonstrated to modulate behavior in classical animal models of depression. Moreover, selective adenosine receptor antagonists are being assessed for their antidepressant effects in animal studies. This review focuses on how caffeine and selective adenosine antagonists can improve different aspects of depression in humans, as well as in animal models. The effects on motivational symptoms of depression such as anergia, fatigue, and psychomotor slowing receive particular attention. Thus, the ability of adenosine receptor antagonists to reverse the anergia induced by dopamine antagonism or depletion is of special interest. In conclusion, although further studies are needed, it appears that caffeine and selective adenosine receptor antagonists could be therapeutic agents for the treatment of motivational dysfunction in depression.»

2018 Association of Coffee and Tea with Ferritin: Data from the Korean National Health and Nutrition Examination Survey (IV and V)

«RESULTS: The general characteristics of the participants according to coffee intake are summarized in Table 1. Subjects of both sexes with higher coffee intakes had a higher BMI, higher education level, and higher smoking rate, together with a lower prevalence of hypertension and diabetes mellitus. The women with higher coffee intake were also younger, and had higher alcohol intake, and had higher levels of physical activity.»

2004 Comparison of caffeine-induced changes in cerebral blood flow and middle cerebral artery blood velocity shows that caffeine reduces middle cerebral...

"Changes in cerebral blood flow (CBF) can be assessed directly with xenon clearance (XeC) or indirectly by measuring changes in middle cerebral artery blood velocity (Vmca) with transcranial Doppler (TCD). The aim of this study was to compare the changes in CBF and Vmca following caffeine ingestion. Nineteen patients (age 48-86, recovering from an acute stroke) and ten controls (age 52-85) were each studied twice. Bilateral measurements of CBF and Vmca were made before and after ingestion of 250 mg caffeine or matched placebo. The percentage change in CBF and Vmca after caffeine was calculated. Full results (CBF and Vmca) were obtained from 14 patients and 9 controls. There was no significant difference between patients and controls, so results were combined. Caffeine reduced CBF by 22% (95% confidence interval (CI) = 17% to 28%) and reduced Vmca by 13% (95% CI = 10% to 17%). The fall in Vmca was significantly less than that in CBF (p = 0.0016), showing that caffeine reduces mca diameter. Analysis based on Poiseuille flow in the arterioles suggests that caffeine reduced arteriole diameter by 5.9% (95% CI = 4.6% to 7.3%) and mca diameter by 4.3% (95% CI = 2.0% to 6.6%). TCD is being used as an alternative to XeC for assessing the effect of vasoconstrictor and vasodilators on CBF. This study has demonstrated that in mca diameter can be changed by the vasoactive agents, and that changes in Vmca do not necessarily reflect changes in CBF."

2004 Physiologic effects of caffeine on cross-country runners.

«This study determined the physiological effects of caffeine on cross-country runners during submaximal exercise. Ten college-age subjects (5 women; 5 men) volunteered to participate in this study. After completing a VO2max test, each subject completed 2 30-minute runs at 70% VO2max on the treadmill, 1 after ingesting caffeine and the other after ingesting a placebo. A caffeine dosage of 7 mg.kg(-1) of body weight was administered. The same dosage of vitamin C was used as a placebo. The order of treatments was randomly assigned, and the trials followed a double-blind format. The physiological data were analyzed using a repeated measures analysis of variance (SPSS). Tidal volume (TV), alveolar ventilation (VA), and rating of perceived exertion (RPE) were significantly different (p < 0.05) between treatment and control groups. The results suggest that the ingestion of caffeine at 7 mg.kg(-1) of body weight prior to submaximal running might provide a modest ergogenic effect via improved respiratory efficiency and a psychological lift.»

2006 Challenging sleep in aging: the effects of 200 mg of caffeine during the evening in young and middle-aged moderate caffeine consumers.

«The aim of this study was to evaluate the effects of a 200-mg administration of caffeine on polysomnographic sleep variables and quantitative sleep electroencephalography (EEG) in 12 young (20-30 years) and 12 middle-aged (40-60 years) moderate caffeine consumers (one to three cups of coffee per day). All subjects were submitted to both a caffeine (200 mg) and placebo (lactose) condition in a double-blind cross-over design. The conditions were separated by 1 week. Compared with the placebo condition, the evening ingestion of caffeine lengthened sleep latency, reduced sleep efficiency, and decreased sleep duration and amount of stage 2 sleep in both age groups. Caffeine also reduced spectral power in delta frequencies in frontal, central and parietal brain areas, but not in prefrontal (PF) and occipital regions. Moreover, caffeine increased spectral power in beta frequencies in frontal and central brain areas in both age groups. A suppression of spectral power in the PF area in low delta frequencies (0.5-1.00 Hz) and a rise in spectral power in the parietal region in high alpha (10.00-12.00 Hz) and beta frequencies (17.00-21.00, 23.00-25.00, 27.00-29.00 Hz) occurred solely in middle-aged subjects. No such changes were noticeable in young subjects. Generally, caffeine produced similar effects in young and middle-aged subjects. Only a few frequency bins showed more effects of caffeine in middle-aged subjects compared with young subjects. Furthermore, sleep EEG results do not entirely support the hypothesis that caffeine fully mimics the effects of a reduction of homeostatic sleep propensity when following a normal sleep-wake cycle.»

2010 Caffeine and adenosine.

«Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (AR): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PD) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of AR, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve AR will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine.»

«Endogenous adenosine, through A1 AR, inhibits long-term synaptic plasticity phenomena, such as long term potentiation (LTP) [47], long term depression (LTD), and depotentiation [48]. In accordance, A1 AR antagonists have for a long time been proposed to treat
memory disorders [49]. C»

2010 Caffeine intake and dementia: systematic review and meta-analysis.

Caffeine intake and dementia: systematic review and meta-analysis. The outcomes of the studies considered for meta-analysis were Alzheimer's disease in four studies, dementia or cognitive impairment in two studies, and cognitive decline in three studies. The summary relative risk (RR) for the association between caffeine intake and different measures of cognitive impairment/decline was 0.84 [95% Confidence Interval (95% CI): 0.72-0.99; I2=42.6%]. When considering only the cohort studies, the summary RR was 0.93 (95% CI: 0.83-1.04, I2= 0.0%), and 0.77 (95% CI: 0.63-0.95, I2= 34.7%), if the most influential study was excluded.

1990 Caffeine and human cerebral blood flow: a positron emission tomography study.

"Positron emission tomography (PET) was used to quantify the effect of caffeine on whole brain and regional cerebral blood flow (CBF) in humans. A mean dose of 250 mg of caffeine produced approximately a 30% decrease in whole brain CBF; regional differences in caffeine effect were not observed. Pre-caffeine CBF strongly influenced the magnitude of the caffeine-induced decrease. Caffeine decreased paCO2 and increased systolic blood pressure significantly; the change in paCO2 did not account for the change in CBF. Smaller increases in diastolic blood pressure, heart rate, plasma epinephrine and norepinephrine, and subjectively reported anxiety were also observed."

2011 [Dietary flavonoids and human health].

[Dietary flavonoids and human health].

2011 Insulin effects in muscle and adipose tissue.

Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S52-9. doi: 10.1016/S0168-8227(11)70014-6. Review

2014 The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption!

Ascorbate acts to stimulate transferrin-dependent iron uptake.

2014 Strategies to improve running economy.

«Running economy (RE) represents a complex interplay of physiological and biomechanical factors that is typically defined as the energy demand for a given velocity of submaximal running and expressed as the submaximal oxygen uptake (VO2) at a given running velocity. This review considered a wide range of acute and chronic interventions that have been investigated with respect to improving economy by augmenting one or more components of the metabolic, cardiorespiratory, biomechanical or neuromuscular systems. Improvements in RE have traditionally been achieved through endurance training. Endurance training in runners lead to a wide range of physiological responses, and it is very likely that these characteristics of running training will influence RE. Training history and training volume have been suggested to be important factors in improving RE, while uphill and level-ground high-intensity interval training represent frequently prescribed forms of training that may elicit further enhancements in economy. More recently, research has demonstrated short-term resistance and plyometric training has resulted in enhanced RE. This improvement in RE has been hypothesized to be a result of enhanced neuromuscular characteristics. Altitude acclimatization results in both central and peripheral adaptations that improve oxygen delivery and utilization, mechanisms that potentially could improve RE. Other strategies, such as stretching should not be discounted as a training modality in order to prevent injuries; however, it appears that there is an optimal degree of flexibility and stiffness required to maximize RE. Several nutritional interventions have also received attention for their effects on reducing oxygen demand during exercise, most notably dietary nitrates and caffeine. It is clear that a range of training and passive interventions may improve RE, and researchers should concentrate their investigative efforts on more fully understanding the types and mechanisms that affect RE and the practicality and extent to which RE can be improved outside the laboratory.»

2015 The evaluation of inflammatory and oxidative stress biomarkers on coffee-diabetes association: results from the 10-year follow-up of the ATTICA Stu...

«During follow-up, 191 incident cases of diabetes were documented (incidence 13.4% in men and 12.4% in women). After various adjustments, individuals who consumed ⩾250 ml of coffee (≈1.5cup) had 54% lower odds of developing diabetes (95% confidence interval: 0.24, 0.90), as compared with abstainers. A dose-response linear trend between coffee drinking and diabetes incidence was also observed (P for trend=0.017). When controlling for several oxidative stress and inflammatory biomarkers, the inverse association between habitual coffee drinking and diabetes was found to be mediated by serum amyloid-A levels.»

«This work highlights the significance of long-term habitual coffee drinking against diabetes onset. The anti-inflammatory effect of several coffee components may be responsible for this protection.»

«Caffeine has been also found to stimulate pancreatic
insulin secretion and CGA is believed to act as a potent inhibitor of
glucose-6-phosphatase, which releases glucose to circulation, and, when abnormal, disturbs normoglycaemia. Both caffeine and CGA
decrease glucose gastric absorption, modulating GIP and GLP-1 secretion.»

«CGA has been shown to inhibit the activation of NF-κb in cultured cells.»

2017 Caffeine intake increases plasma ketones: an acute metabolic study in humans.

«Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.»

2017 Role of D-galactose-induced brain aging and its potential used for therapeutic interventions.

The effects of D-galactose-induced mitochondrial dysfunction and oxidative stress in the brain. D-galactose oxidized by galactose oxidase to form hydrogen peroxide (H2O2), leading to decrease in superoxide dismutase (SOD) (Hsieh et al., 2009). Increased H2O2 reacts with a reduced form of iron (Fe) to form hydroxide ions (OH-). The H2O2 and OH are both types of reactive oxygen species (ROS) and along with others can cause lipid peroxidation in the cell membranes and impair redox homeostasis, leading to neuronal damage.

In addition, several studies described that D-galactose induced the accumulation of brain mitochondrial DNA mutation (Chen et al., 2011; Du et al., 2012; Du et al., 2015; Zeng et al., 2014) through: 1) decreasing DNA-repairing enzymes (OGG1, pol ᵧ) (Chen et al., 2011), and 2) common deletion of mitochondrial DNA and impairing mitochondrial structures via the NOX-dependent pathway (Du et al., 2015).

Effect of D-galactose-induced apoptosis in the brain. D-galactose
promoted the apoptotic process (Qian et al., 2008). In addition to apoptosis, D-galactose promoted neuro-inflammation and neurodegeneration (Cui et al., 2006). The dosage from which D-galactose started inducing apoptosis was 100 mg- 500 mg/kg/day, duration was from 6 weeks to 9 weeks. (as shown in Table 2)

Effect of D-galactose-induced brain inflammation. D-galactose started inducing inflammation at a dosage of 50mg-180mg/kg/day and duration was from 6 weeks to 60 days.

Therapeutic approaches to brain mitochondrial aging induced by D-galactose:

The first one used R-alpha-lipoic acid which is an antioxidant abundant in yeast, liver, kidney, spinach, broccoli, and potatoes, to treat mitochondrial dysfunction (Long et al., 2007). One of the studies stated that 100 mg/kg/day of R-alpha-lipoic acid is used for prevention but not for intervention, dosage should be increased up to 180mg/kg/day (Inman et al., 2013).

Carvidilol, pioglitazone, curcumin and hesperidin have an antioxidant effect. These drugs have been used as an intervention to reverse D-galactose-induced mitochondrial dysfunction in a dose dependent manner.

The other therapeutic approaches to improve cognition with a dose-independent manner in the D-galactose model were fibroblast growth factor 21 (FGF21), salidroside, and tetrahydropalmatine (Banji et al., 2014; Gao et al., 2015; Kumar et al., 2009; Prakash and Kumar, 2013; Qu et al., 2016; Yang et al., 2016; Yu et al., 2015).

FGF21 acts on its receptors and prevents D-galactose-induced spatial learning and memory impairment by attenuating oxidative stress, inflammatory markers and renovating the activities of antioxidant enzymes and decreasing AGE formation, and TChE activity (Yu et al., 2015).

Many studies have proved that a daily intake of caffeine ameliorated cognitive decline in “non-demented” elderly men and women by the mechanism of reducing synaptic dysfunction, and the reduction in oxidative stress, apoptosis, neuro-inflammation and neurodegeneration (Ritchie et al., 2007; van Gelder et al., 2007).

1980 Effects of caffeine on anterior pituitary and thyroid function in the rat.

«We studied the effects of acute, intraperitoneal administration of caffeine on serum thyrotropin (TSH), growth hormone, prolactin, thyroxine and 3,3',5-triiodothyronine in rats. Caffeine lowered serum TSH and GH in a dose-dependent manner with ED50 values of 30 and approximately 50 mg/kg, respectively. TSH levels were depressed 1 to 6 hr after injection and correlated with serum caffeine levels greater than 20 micrograms/ml. The decrease in serum TSH was followed by decreases in serum 3,3',5-triiodothyroxine and thyroxine 4 hr after caffeine administration. Theophylline and theobromine had effects similar to those of caffeine on hormone levels. Caffeine did not significantly affect hormone secretion when incubated directly with rat pituitaries in vitro. Administration of antisomatostatin antiserum to rats blocked the inhibitory effects of caffeine on serum GH levels, suggesting that caffeine inhibits GH and TSH secretion by releasing hypothalamic somatostatin.»

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