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Hypothalamic integration of immune function and metabolism.

The immune and neuroendocrine systems are closely involved in the regulation of metabolism at peripheral and central hypothalamic levels. In both physiological (meals) and pathological (infections, traumas and tumors) conditions immune cells are activated responding with the release of cytokines and other immune mediators (afferent signals). In the hypothalamus (central integration), cytokines influence metabolism by acting on nucleus involved in feeding and homeostasis regulation leading to the acute phase response (efferent signals) aimed to maintain the body integrity. Peripheral administration of cytokines, inoculation of tumor and induction of infection alter, by means of cytokine action, the normal pattern of food intake affecting meal size and meal number suggesting that cytokines acted differentially on specific hypothalamic neurons. The effect of cytokines-related cancer anorexia is also exerted peripherally. Increase plasma concentrations of insulin and free tryptophan and decrease gastric emptying and d-xylose absorption. In addition, in obesity an increase in interleukin (IL)-1 and IL-6 occurs in mesenteric fat tissue, which together with an increase in corticosterone, is associated with hyperglycemia, dyslipidemias and insulin resistance of obesity-related metabolic syndrome. These changes in circulating nutrients and hormones are sensed by hypothalamic neurons that influence food intake and metabolism. In anorectic tumor-bearing rats, we detected upregulation of IL-1beta and IL-1 receptor mRNA levels in the hypothalamus, a negative correlation between IL-1 concentration in cerebro-spinal fluid and food intake and high levels of hypothalamic serotonin, and these differences disappeared after tumor removal. Moreover, there is an interaction between serotonin and IL-1 in the development of cancer anorexia as well as an increase in hypothalamic dopamine and serotonin production. Immunohistochemical studies have shown a decrease in neuropeptide Y (NPY) and dopamine (DA) and an increase in serotonin concentration in tumor-bearing rats, in first- and second-order hypothalamic nuclei, while tumor resection reverted these changes and normalized food intake, suggesting negative regulation of NPY and DA systems by cytokines during anorexia, probably mediated by serotonin that appears to play a pivotal role in the regulation of food intake in cancer. Among the different forms of therapy, nutritional manipulation of diet in tumor-bearing state has been investigated. Supplementation of tumor bearing rats with omega-3 fatty acid vs. control diet delayed the appearance of tumor, reduced tumor-growth rate and volume, negated onset of anorexia, increased body weight, decreased cytokines production and increased expression of NPY and decreased alpha-melanocyte-stimulating hormone (alpha-MSH) in hypothalamic nuclei. These data suggest that omega-3 fatty acid suppressed pro-inflammatory cytokines production and improved food intake by normalizing hypothalamic food intake-related peptides and point to the possibility of a therapeutic use of these fatty acids. The sum of these data support the concept that immune cell-derived cytokines are closely related with the regulation of metabolism and have both central and peripheral actions, inducing anorexia via hypothalamic anorectic factors, including serotonin and dopamine, and inhibiting NPY leading to a reduction in food intake and body weight, emphasizing the interconnection of the immune and neuroendocrine systems in regulating metabolism during infectious process, cachexia and obesity.

Vitamin D deficiency is a global health problem, its role as an immune modulator has been recently emphasized.

Vitamin D deficiency is a global health problem, its role as an immune modulator has been recently emphasized. The evidence is increasingly pointing towards vitamin D significant role in reducing the incidence of autoimmune diseases. However, at this time the research on its role in autoimmune and thyroid disease is not conclusive.

We aimed to examine the relationship between hypothyroidism and vitamin D deficiency and to clarify the relation between serum calcium levels with hypothyroid disease.

Second-tier natural antidepressants: review and critique

Both supplements of L-tryptophan and 5-HTP have been used in the treatment of depression, but the use of 5-HTP may offer the advantage of bypassing the conversion of L-tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. Tryptophan hydroxylase can be inhibited by numerous factors, including stress, insulin resistance, vitamin B6 deficiency, and insufficient magnesium... Moreover, 5-HTP easily crosses the blood–brain barrier, and unlike L-tryptophan, does not require a transport molecule to enter the central nervous system (Green et al., 1980; Maes et al., 1990). Besides serotonin, other neurotransmitters and hormones, such as melatonin, dopamine, norepinephrine, and beta-endorphin have also been shown to increase following oral administration of 5-HTP. All of these compounds are thought to be involved in the regulation of mood as well as sleep and may represent mechanistic pathways stimulated by 5-HTP administration.

The therapeutic potential for tryptophan and melatonin: possible roles in depression, sleep, Alzheimer's disease and abnormal aging

Evidence suggests that stress and/or a dietary lack of tryptophan may make deficiencies of serotonin and melatonin common. In addition, older animals and human beings have a reduced ability to synthesize melatonin. Disorders of melatonin levels and rhythms are suggested to be a cause of affective disease, abnormal sleep, Alzheimer's disease, and some age related disorders. If these ideas prove to be true, then preventive measures are possible.

L-tryptophan administered to chronic sleep-onset insomniacs: late-appearing reduction of sleep latency

The effects of 3 g L-tryptophan on sleep, performance, arousal threshold, and brain electrical activity during sleep were assessed in 20 male, chronic sleep-onset insomniacs (mean age 20.3 +/- 2.4 years). Following a sleep laboratory screening night, all subjects received placebo for 3 consecutive nights (single-blind), ten subjects received L-tryptophan, and ten received placebo for 6 nights (double-blind). All subjects received placebo on 2 withdrawal nights (single-blind). There was no effect of L-tryptophan on sleep latency during the first 3 nights of administration. On nights 4-6 of administration, sleep latency was significantly reduced. Unlike benzodiazepine hypnotics, L-tryptophan did not alter sleep stages, impair performance, elevate arousal threshold, or alter brain electrical activity during sleep.

Effects of L-tryptophan on sleepiness and on sleep

Over the past 20 yr, 40 controlled studies have been described concerning the effects of L-tryptophan on human sleepiness and/or sleep. The weight of evidence indicates that L-tryptophan in doses of 1 g or more produces an increase in rated subjective sleepiness and a decrease in sleep latency (time to sleep). There are less firm data suggesting that L-tryptophan may have additional effects such as decrease in total wakefulness and/or increase in sleep time. Best results (in terms of positive effects on sleep or sleepiness) have been found in subjects with mild insomnia, or in normal subjects reporting a longer-than-average sleep latency. Mixed or negative results occur in entirely normal subjects--who are not appropriate subjects since there is no room for improvement. Mixed results are also reported in severe insomniacs and in patients with serious medical or psychiatric illness.

Effects of tryptophan loading on human cognition, mood, and sleep

Modulating central serotonergic function by acute tryptophan depletion (ATD) has provided the fundamental insights into which cognitive functions are influenced by serotonin. It may be expected that serotonergic stimulation by tryptophan (Trp) loading could evoke beneficial behavioural changes that mirror those of ATD. The current review examines the evidence for such effects, notably those on cognition, mood and sleep. Reports vary considerably across different cognitive domains, study designs, and populations. It is hypothesised that the effects of Trp loading on performance may be dependent on the initial state of the serotonergic system of the subject. Memory improvements following Trp loading have generally been shown in clinical and sub-clinical populations where initial serotonergic disturbances are known. Similarly, Trp loading appears to be most effective for improving mood in vulnerable subjects, and improves sleep in adults with some sleep disturbances. Research has consistently shown Trp loading impairs psychomotor and reaction time performance, however, this is likely to be attributed to its mild sedative effects. (c) 2009 Elsevier Ltd. All rights reserved.

Other benefits of melatonin include general neuroprotective effects, as melatonin is a powerful antioxidant

Neuroprotection:  Other benefits of melatonin include general neuroprotective effects, as melatonin is a powerful antioxidant. Melatonin also has several anti-cancer properties, and is currently being investigated for its role in fighting breast cancer.  “Both in vitro studies and in vivo studies have shown that melatonin is a potent scavenger of the highly toxic hydroxyl radical and other oxygen- centered radicals, suggesting that it has actions not mediated by receptors.31 In one study, melatonin seemed to be more effective than other known anti- oxidants (e.g., mannitol, glutathione, and vitamin E) in protecting against oxidative damage. There- fore, melatonin may provide protection against dis- eases that cause degenerative or proliferative changes by shielding macromolecules, particularly DNA, from such injuries. However, these antioxidant effects require concentrations of melatonin that are much higher than peak nighttime serum concentrations. Thus, the antioxidant effects of melatonin in humans probably occur only at pharmacologic concentrations….The decrease in nighttime serum melatonin concentrations that occurs with aging, together with its multiple biologic effects, has led several investigators to suggest that melatonin has a role in aging and age-related diseases. Studies in rats and mice suggest that diminished melatonin secretion may be associated with an acceleration of the aging process. Melatonin may provide protection against aging through attenuation of the effects of cell damage induced by free radicals or through immunoenhancement. However, the age-related reduction in nighttime melatonin secretion could well be a consequence of the aging process rather than its cause, and there are no data supporting an antiaging effect of melatonin in humans.”

A practical approach to circadian rhythm sleep disorders

Light suppresses melatonin while darkness stimulates its synthesis. Many people have trouble falling asleep. Delayed sleep phase syndrome results in late sleep onset, despite normal sleep architecture and total sleep duration. Melatonin has been shown to improve sleep latency (the time it takes to fall asleep) in several randomized controlled studies. Rather than immediately prior to sleeping, melatonin works best when given two hours before sleeping. Melatonin is also useful for jet lag, irregular sleep-wake rhythms, and shift work sleep disorder.  Exogenously administered melatonin has phase shifting properties, and the effect follows a phase- response curve (PRC) that is about 12 h out of phase with the PRC [phase response curve] of light Melatonin administered in the afternoon or early evening will phase advance the circadian rhythm, whereas melatonin administered in the morning will phase delay the circadian rhythm (Fig. 2). The magnitude of phase shifts is time-dependent, and the maximal phase shifts result when melatonin is scheduled around dusk or dawn. The effect of exogenous melatonin is minimal when administered during the night, at least during the first-half of the night.

Melatonin in nonapnea sleep disorders

Nonapnea sleep disorders:  Nonapnea sleep disorder In humans, melatonin secretion increases soon after the onset of darkness, peaks in the middle of the night (between 2 and 4 a.m.), and gradually falls during the second half of the night

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

The endogenous estrogen 17beta-estradiol can be metabolized to 16alpha-hydroxyestrone (16alpha OHE1) or 2-hydroxyestrone (2OHE1). In contrast to 2OHE1, 16alpha OHE1 is highly estrogenic and has been found to enhance the proliferation of estrogen-sensitive breast cancer cells in culture. It has been hypothesized that shifting the metabolism of 17beta-estradiol toward 2OHE1 and away from 16alphaOHE1 could decrease the risk of estrogen-sensitive cancers, such as breast cancer. In a small clinical trial, increasing cruciferous vegetable intake of healthy postmenopausal women for four weeks increased urinary 2OHE1:16alpha OHE1ratios, suggesting that high intakes of cruciferous vegetables can shift estrogen metabolism.

Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

Ubiquinone is a carrier of the mitochondrial respiratory chain which regulates oxidative phosphorylation: it also acts as a membrane stabilizer preventing lipid peroxidation. In man the quinone ring originates from tyrosine, while the formation of the polyisoprenoid lateral chain starts from acetyl CoA and proceeds through mevalonate and isopentenylpyrophosphate; this biosynthetic pathway is the same as the cholesterol one. We therefore performed this study to evaluate whether statins (hypocholesterolemic drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase) modify blood levels of ubiquinone. Thirty unrelated outpatients with primary hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 3-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, and at 45 and 90 days: total plasma cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Apo A1, Apo B and CoQ10 in plasma and in platelets. In the S group, there was a marked decrease in total cholesterol low-density lipoprotein-cholesterol and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of plasma CoQ10 (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors

The biosynthetic pathway of the CoQ polyisoprenoid side chain, starting from acetyl-CoA and proceeding through mevalonate and isopentenylpyrophosphate, is the same as that of cholesterol. We performed this study to evaluate whether vastatins (hypocholesterolemic drugs that inhibit HMG-CoA reductase) modify blood levels of ubiquinone. Thirty-four unrelated outpatients with hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 6-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, 45, 90, 135 and 180 days: total plasma cholesterol (TC), HDL-cholesterol, LDL-cholesterol (LDL-C), triglycerides (TG), apo A1, apo B and CoQ10 in plasma and platelets. In the S group, there was a marked decrease in TC and LDL-C (from 290.3 mg/dl to 228.7 mg/dl for TC and from 228.7 mg/dl to 167.6 mg/dl for LDL-C) and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of CoQ10 in plasma (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg). This study demonstrates that simvastatin lowers both LDL-C and apo B plasma levels together with the plasma and platelet levels of CoQ10, and that CoQ10 therapy prevents both plasma and platelet CoQ10 decrease, without affecting the cholesterol lowering effect of simvastatin.

Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex vivo

The statins or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors are the most effective drugs in lowering serum low density lipoprotein (LDL) concentration. They decrease cardiovascular morbidity and mortality of hypercholesterolemic patients, even in primary prevention. Large controlled prospective studies have shown that statins as a group improve the prognosis of coronary heart disease (CHD) patients. The HMG-CoA reductase inhibitors affect competitively the early key enzyme of the mevalonate pathway (Fig. 1), thus inhibiting the synthesis of cholesterol and other non-sterol end products. One of them is coenzyme Q10 (2,3-dimethoxy-5-methyl-6-decaprenyl benzoquinone), also known as ubiquinone. It may be estimated that on a normal diet, 60% of plasma ubiquinone is endogenous.

Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study

Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQ10).