Nitric Oxide as a Determinant of Human Longevity and Health Span.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage-L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

Tryptophan in Nutrition and Health 2.0.

This editorial summarizes the eight articles that have been collected for the Special Issue entitled "Tryptophan in Nutrition and Health 2 [...].

Tryptophan in Nutrition and Health.

Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...].

Indoles as essential mediators in the gut-brain axis. Their role in Alzheimer's disease.

Sporadic late-onset Alzheimer's disease (AD) is the most frequent cause of dementia associated with aging. Due to the progressive aging of the population, AD is becoming a healthcare burden of unprecedented proportions. Twenty years ago, it was reported that some indole molecules produced by the gut microbiota possess essential biological activities, including neuroprotection and antioxidant properties. Since then, research has cemented additional characteristics of these substances, including anti-inflammatory, immunoregulatory, and amyloid anti-aggregation features. Herein, we summarize the evidence supporting an integrated hypothesis that some of these substances can influence the age of onset and progression of AD and are central to the symbiotic relationship between intestinal microbes and the brain. Studies have shown that some of these substances' activities result from interactions with biologically conserved pathways and with genetic risk factors for AD. By targeting multiple pathologic mechanisms simultaneously, certain indoles may be excellent candidates to ameliorate neurodegeneration. We propose that management of the microbiota to induce a higher production of neuroprotective indoles (e.g., indole propionic acid) will promote brain health during aging. This area of research represents a new therapeutic paradigm that could add functional years of life to individuals who would otherwise develop dementia.

Evidence for lymphatic Aß clearance in Alzheimer's transgenic mice.

Evidence has shown that lymphatic drainage contributes to removal of debris from the brain but its role in the accumulation of amyloid ß peptides (Aß) has not been demonstrated. We examined the levels of various forms of Aß in the brain, plasma and lymph nodes in a transgenic model of Alzheimer's disease (AD) at different ages. Herein, we report on the novel finding that Aß is present in the cervical and axillary lymph nodes of AD transgenic mice and that Aß levels in lymph nodes increase over time, mirroring the increase of Aß levels observed in the brain. Aß levels in lymph nodes were significantly higher than in plasma. At age 15.5months, there was a significant increase of monomeric soluble Aß40 (p=0.003) and Aß42 (p=0.05) in the lymph nodes over the baseline values measured at 6months of age. In contrast, plasma levels of Aß40 showed no significant changes (p=0.68) and plasma levels Aß42 significantly dropped (p=0.02) at the same age. Aß concentration was low to undetectable in splenic lymphoid tissue and several other control tissues including heart, lung, liver, kidneys and intestine of the same animals, strongly suggesting that Aß peptides in lymph nodes are derived from the brain.

The Tryptophan Metabolite Indole-3-Propionic Acid Raises Kynurenic Acid Levels in the Rat Brain In Vivo.

Alterations in the composition of the gut microbiota may be causally associated with several brain diseases. Indole-3-propionic acid (IPrA) is a tryptophan-derived metabolite, which is produced by intestinal commensal microbes, rapidly enters the circulation, and crosses the blood-brain barrier. IPrA has neuroprotective properties, which have been attributed to its antioxidant and bioenergetic effects. Here, we evaluate an alternative and/or complementary mechanism, linking IPrA to kynurenic acid (KYNA), another neuroprotective tryptophan metabolite. Adult Sprague-Dawley rats received an oral dose of IPrA (200 mg/kg), and both IPrA and KYNA were measured in plasma and frontal cortex 90 minutes, 6 or 24 hours later. IPrA and KYNA levels increased after 90 minutes and 6 hours (brain IPrA: ~56- and ~7-fold; brain KYNA: ~4- and ~3-fold, respectively). In vivo microdialysis, performed in the medial prefrontal cortex and in the striatum, revealed increased KYNA levels (~2.5-fold) following the administration of IPrA (200 mg/kg, p.o), but IPrA failed to affect extracellular KYNA when applied locally. Finally, treatment with 100 or 350 mg IPrA, provided daily to the animals in the chow for a week, resulted in several-fold increases of IPrA and KYNA levels in both plasma and brain. These results suggest that exogenously supplied IPrA may provide a novel strategy to affect the function of KYNA in the mammalian brain.

Copper-mediated ß-amyloid toxicity and its chelation therapy in Alzheimer's disease.

The link between bio-metals, Alzheimer's disease (AD), and its associated protein, amyloid-ß (Aß), is very complex and one of the most studied aspects currently. Alzheimer's disease, a progressive neurodegenerative disease, is proposed to occurs due to the misfolding and aggregation of Aß. Dyshomeostasis of metal ions and their interaction with Aß has largely been implicated in AD. Copper plays a crucial role in amyloid-ß toxicity, and AD development potentially occurs through direct interaction with the copper-binding motif of APP and different amino acid residues of Aß. Previous reports suggest that high levels of copper accumulation in the AD brain result in modulation of toxic Aß peptide levels, implicating the role of copper in the pathophysiology of AD. In this review, we explore the possible mode of copper ion interaction with Aß, which accelerates the kinetics of fibril formation and promote amyloid-ß mediated cell toxicity in Alzheimer's disease and the potential use of various copper chelators in the prevention of copper-mediated Aß toxicity. KEYWORDS: Short Twitter Statement: Authors explore copper ion interaction w/ Aß and kinetics of fibril formation in promoting amyloid-ß mediated cell toxicity in Alzheimer's disease and the potential use of copper chelators in the prevention of copper-mediated Aß toxicity. SHORT TWITTER STATEMENT: Authors explore copper ion interaction w/Aß and kinetics of fibril formation in promoting amyloid-ß mediated cell toxicity in Alzheimer's disease and the potential use of copper chelators in the prevention of copper-mediated Aß toxicity.

Flavonoids as Promising Neuroprotectants and Their Therapeutic Potential against Alzheimer's Disease.

Alzheimer's disease (AD) is one of the serious and progressive neurodegenerative disorders in the elderly worldwide. Various genetic, environmental, and lifestyle factors are associated with its pathogenesis that affect neuronal cells to degenerate over the period of time. AD is characterized by cognitive dysfunctions, behavioural disability, and psychological impairments due to the accumulation of amyloid beta (Aß) peptides and neurofibrillary tangles (NFT). Several research reports have shown that flavonoids are the polyphenolic compounds that significantly improve cognitive functions and inhibit or delay the amyloid beta aggregation or NFT formation in AD. Current research has uncovered that dietary use of flavonoid-rich food sources essentially increases intellectual abilities and postpones or hinders the senescence cycle and related neurodegenerative problems including AD. During AD pathogenesis, multiple signalling pathways are involved and to target a single pathway may relieve the symptoms but not provides the permanent cure. Flavonoids communicate with different signalling pathways and adjust their activities, accordingly prompting valuable neuroprotective impacts. Flavonoids likewise hamper the movement of obsessive indications of neurodegenerative disorders by hindering neuronal apoptosis incited by neurotoxic substances. In this short review, we briefly discussed about the classification of flavonoids and their neuroprotective properties that could be used as a potential source for the treatment of AD. In this review, we also highlight the structural features of flavonoids, their beneficial roles in human health, and significance in plants as well as their microbial production.

Thyrotropin powers human mitochondria.

Here we demonstrate that the neuropeptide hormone thyrotropin (TSH), which controls thyroid hormone production, exerts a major nonclassical function in mitochondrial biology. Based on transcriptional, ultrastructural, immunohistochemical, and biochemical evidence, TSH up-regulates mitochondrial biogenesis and consequently activity in organ-cultured normal human epidermis in situ. Mitochondrial activity was assessed by measuring 2 key components of the respiratory chain. The abundance of mitochondria was assessed employing 2 independent morphological techniques: counting their numbers in human epidermis by high-magnification light microscopy of skin sections immunostained for mitochondria-selective cytochrome-c-oxidase subunit 1 (MTCO1) and transmission electron microscopy (TEM). Treatment with 10 mU/ml of TSH for 6 d strongly up-regulates the number of light-microscopically visualized, MTCO1-demarcated mitochondria. On the ultrastructural level, TEM confirms that TSH indeed stimulates mitochondrial proliferation and biogenesis in the perinuclear region of human skin epidermal keratinocytes. On the transcriptional level, TSH up-regulates MTCO1 mRNA (quantitative RT-PCR) and significantly enhances complex I and IV (cytochrome-c-oxidase) activity. This study pioneers the concept that mitochondrial energy metabolism and biogenesis in a normal, prototypic human epithelial tissue underlies potent neuroendocrine controls and introduces human skin organ culture as a clinically relevant tool for further exploring this novel research frontier in the control of mitochondrial biology.

A simple assay for the study of human hair follicle damage induced by ionizing irradiation.

Due to its rapidly proliferating matrix keratinocytes, the hair follicle is highly sensitive to ionizing irradiation (IR)-induced skin damage and thus an instructive and clinically relevant model organ for investigating the effects of IR on rapidly dividing epithelial-mesenchymal interaction systems. Here, we have assessed the impact of IR on organ-cultured human scalp hair follicles. We show that IR significantly inhibits the proliferation and induces apoptosis of hair follicle matrix keratinocytes, disrupts normal hair follicle pigmentation, and upregulates a number of quantitative toxicity and viability markers (oxidative stress indicators, DNA oxidative damage, LDH release). This introduces human hair follicle organ culture as an excellent novel research tool for radiobiology and invites exploitation as a preclinical assay system for testing candidate radioprotectants.

The mineralocorticoid receptor as a novel player in skin biology: beyond the renal horizon?

The mineralocorticoid receptor (MR) and its ligand aldosterone regulate renal sodium reabsorption and blood pressure and much knowledge has been accumulated in MR physiopathology, cellular and molecular targets. In contrast, our understanding of this hormonal system in non-classical targets (heart, blood vessels, neurons, keratinocytes...) is limited, particularly in the mammalian skin. We review here the few available data that point on MR in the skin and that document cutaneous MR expression and function, based on mouse models and very limited observations in humans. Mice that overexpress the MR in the basal epidermal keratinocytes display developmental and post-natal abnormalities of the epidermis and hair follicle, raising exciting new questions regarding skin biology. The MR as a transcription factor may be an unexpected novel player in regulating keratinocyte and hair physiology and pathology. Because its activating ligand also includes glucocorticoids, that are widely used in dermatology, we propose that the MR may be also involved in the side-effects of corticoids, opening novel options for therapeutical intervention.

Leptin and the skin: a new frontier.

Here, we examine the currently available information which supports that the adipokine, leptin, is a major player in the biology and pathology of mammalian skin and its appendages. Specifically, the potent metabolic effects of leptin and its mimetics may be utilized to improve, preserve and restore skin regeneration and hair cycle progression, and may halt or even partially reverse some aspects of skin ageing. Since leptin can enhance mitochondrial activity and biogenesis, this may contribute to the wound healing-promoting and hair growth-modulatory effects of leptin. Leptin dependent intracellular signalling by the Janus kinase 2 dependent signal transducer and activator of transcription 3, adenosine monophosphate kinase, and peroxisome proliferator-activated receptor (PPAR) gamma coactivator/PPAR converges to mediate mitochondrial metabolic activation and enhanced cell proliferation which may orchestrate the potent developmental, trophic and protective effects of leptin. Since leptin and leptin mimetics have already been clinically tested, investigative dermatology is well-advised to place greater emphasis on the systematic exploration of the cutaneous dimensions and dermatological potential of this pleiotropic hormone.

Pathophysiology of depression: role of sleep and the melatonergic system.

Profound disturbances in sleep architecture occur in major depressive disorders (MDD) and in bipolar affective disorders. Reduction in slow wave sleep, decreased latency of rapid eye movement (REM) sleep and abnormalities in the timing of REM/non-REM sleep cycles have all been documented in patients with MDD. It is thus evident that an understanding of the basic mechanisms of sleep regulation is essential for an analysis of the pathophysiology of depressive disorders. The suprachiasmatic nucleus (SCN), which functions as the body's master circadian clock, plays a major role in the regulation of the sleep/wakefulness rhythm and interacts actively with the homeostatic processes that regulate sleep. The control of melatonin secretion by the SCN, the occurrence of high concentrations of melatonin receptors in the SCN, and the suppression of electrical activity in the SCN by melatonin all underscore the major influence which this neurohormone has in regulating the sleep/wake cycle. The transition from wakefulness to high sleep propensity is associated with the nocturnal rise of endogenous melatonin secretion. Various lines of evidence show that depressed patients exhibit disturbances in both the amplitude and shape of the melatonin secretion rhythm and that melatonin can improve the quality of sleep in these patients. The choice of a suitable antidepressant that improves sleep quality is thus important while treating a depressive disorder. The novel antidepressant agomelatine, which combines the properties of a 5-HT(2C) antagonist and a melatonergic MT(1)/MT(2) receptor agonist, has been found very effective for resetting the disturbed sleep/wake cycle and in improving the clinical status of MDD. Agomelatine has also been found useful in treating sleep problems and improving the clinical status of patients suffering from seasonal affective disorder.

Melatonin and melatonergic drugs on sleep: possible mechanisms of action.

Pineal melatonin is synthesized and secreted in close association with the light/dark cycle. The temporal relationship between the nocturnal rise in melatonin secretion and the "opening of the sleep gate" (i.e., the increase in sleep propensity at the beginning of the night), coupled with the sleep-promoting effects of exogenous melatonin, suggest that melatonin is involved in the regulation of sleep. The sleep-promoting and sleep/wake rhythm regulating effects of melatonin are attributed to its action on MT(1) and MT(2) melatonin receptors present in the suprachiasmatic nucleus (SCN) of the hypothalamus. Animal experiments carried out in rats, cats, and monkeys have revealed that melatonin has the ability to reduce sleep onset time and increase sleep duration. However, clinical studies reveal inconsistent findings, with some of them reporting beneficial effects of melatonin on sleep, whereas in others only marginal effects are documented. Recently a prolonged-release 2-mg melatonin preparation (Circadin(TM)) was approved by the European Medicines Agency as a monotherapy for the short-term treatment of primary insomnia in patients who are aged 55 or above. Several melatonin derivatives have been shown to increase nonrapid eye movement (NREM) in rats and are of potential pharmacological importance. So far only one of these melatonin derivatives, ramelteon, has received approval from the U.S. Food and Drug Administration to be used as a sleep promoter. Ramelteon is a novel MT(1) and MT(2) melatonergic agonist that has specific effects on melatonin receptors in the SCN and is effective in promoting sleep in experimental animals such as cats and monkeys. In clinical trials, ramelteon reduced sleep onset latency and promoted sleep in patients with chronic insomnia, including an older adult population. Both melatonin and ramelteon promote sleep by regulating the sleep/wake rhythm through their actions on melatonin receptors in the SCN, a unique mechanism of action not shared by any other hypnotics. Moreover, unlike benzodiazepines, ramelteon causes neither withdrawal effects nor dependence. Agomelatine, another novel melatonergic antidepressant in its final phase of approval for clinical use, has been shown to improve sleep in depressed patients and to have an antidepressant efficacy that is partially attributed to its effects on sleep-regulating mechanisms.

Mobile Phone Chips Reduce Increases in EEG Brain Activity Induced by Mobile Phone-Emitted Electromagnetic Fields.

Recent neurophysiological studies indicate that exposure to electromagnetic fields (EMFs) generated by mobile phone radiation can exert effects on brain activity. One technical solution to reduce effects of EMFs in mobile phone use is provided in mobile phone chips that are applied to mobile phones or attached to their surfaces. To date, there are no systematical studies on the effects of mobile phone chip application on brain activity and the underlying neural mechanisms. The present study investigated whether mobile phone chips that are applied to mobile phones reduce effects of EMFs emitted by mobile phone radiation on electroencephalographic (EEG) brain activity in a laboratory study. Thirty participants volunteered in the present study. Experimental conditions (mobile phone chip, placebo chip, no chip) were set up in a randomized within-subjects design. Spontaneous EEG was recorded before and after mobile phone exposure for two 2-min sequences at resting conditions. During mobile phone exposure, spontaneous EEG was recorded for 30 min during resting conditions, and 5 min during performance of an attention test (d2-R). Results showed increased activity in the theta, alpha, beta and gamma bands during EMF exposure in the placebo and no chip conditions. Application of the mobile phone chip reduced effects of EMFs on EEG brain activity and attentional performance significantly. Attentional performance level was maintained regarding number of edited characters. Further, a dipole analysis revealed different underlying activation patterns in the chip condition compared to the placebo chip and no chip conditions. Finally, a correlational analysis for the EEG frequency bands and electromagnetic high-frequency (HF) emission showed significant correlations in the placebo chip and no chip condition for the theta, alpha, beta, and gamma bands. In the chip condition, a significant correlation of HF with the theta and alpha bands, but not with the beta and gamma bands was shown. We hypothesize that a reduction of EEG beta and gamma activation constitutes the key neural mechanism in mobile phone chip use that supports the brain to a degree in maintaining its natural activity and performance level during mobile phone use.

Fine-tuning the amphiphilicity: a crucial parameter in the design of potent alpha-phenyl-N-tert-butylnitrone analogues.

A new series of hydrophilic, lipophilic, and amphiphilic alpha-phenyl-N-tert-butylnitrone (PBN) derivatives were synthesized to explore the relationship between their hydrophilic-lipophilic properties and antioxidant potency. Very potent protective effects of amphiphilic lactobionamide and tris(hydroxymethyl)aminomethane PBN derivatives were observed in mitochondrial preparations, in cell cultures, and in rotifers exposed to unspecific and mitochondria targeted oxidotoxins.

Drug Insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon.

Melatonin, a chronobiotic that participates in the control of the circadian system, is known for its sleep-promoting effects, which include shortening of sleep latency and lengthening of sleep duration. As a result of its short half-life, melatonin does not exhibit undesirable side effects, and its broad applicability for a variety of sleep problems has been the focus of numerous scientific studies. Melatonin has not, however, received regulatory approval from the US FDA as a drug, because it can be sold freely as a food supplement. Consequently, there has been an active search for patentable melatonin receptor ligands in recent years. Ramelteon, an agonist that acts solely on melatonin MT(1) and MT(2) receptors, is of particular interest, and preliminary research indicates that it holds considerable promise for clinical applications. Ramelteon has been shown to induce sleep initiation and maintenance in various animal models and in clinical trials. In chronic insomnia, ramelteon decreases sleep latency and increases total sleep time and sleep efficiency, without causing hangover, addiction or withdrawal effects. Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the suprachiasmatic nucleus. Although ramelteon's metabolism and pharmacokinetics differ from those of melatonin, its safety seems to be sufficient for short-term application. Its long-term effects remain to be determined.

Nitrone Derivatives as Therapeutics: From Chemical Modification to Specific-targeting.

Nitrones have been extensively used for the detection of transient free radicals using electron paramagnetic resonance. Since the mid-80's, nitrones have also been widely used as protective agents against oxidative stress in several biological models. Due to the high potency of nitrones, there has been extensive research on the development of derivatives with improved biological and spin trapping properties as well as enhanced intra-cellular compartmentalization. The chemical and pharmacological properties of nitrones depend mainly on the connectivity as well as on the nature and the position of the substituents on the nitrone group. Therefore, novel bioactive molecules have been designed and the development of specific nitrone derivatives is aimed at providing new therapeutic approaches and perspectives in prevention, treatment and rehabilitation. This review focuses on the effects that are exerted by the most promising nitrone antioxidants that are available. A comprehensive description of the unique molecular mechanism and mediators that are targeted by these compounds is given to guide and enable novel and successful approaches to the treatment of a broad spectrum of diseases associated with stress and aging. New promising nitrone compounds are now available for further development by translational medicine that exert superior bioactivity and efficacy.

Fluorinated amphiphilic amino acid derivatives as antioxidant carriers: a new class of protective agents.

The use of classical antioxidants is limited by their low bioavailabilities, and therefore, high doses are usually required to display significant protective activity. In a recent article (J. Med. Chem. 2003, 46, 5230) we showed that the ability of the alpha-phenyl-N-tert-butylnitrone (PBN) to restore the viability of ATPase-deficient human skin fibroblasts was greatly enhanced by grafting it on a fluorinated amphiphilic carrier. With the aim of extending this concept to other antioxidants, we present here the design, the synthesis, and the physicochemical measurements of a new series of fluorinated amphiphilic antioxidant derivatives. The hydroxyl radical scavenging activity and the radical reducing potency of these newly designed compounds were respectively demonstrated in an ABTS competition and an ABTS(*+) reduction assay. We also showed that the protective effects of amphiphilic antioxidants derived from PBN, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) or lipoic acid (5-[1,2]-dithiolan-3-ylpentanoic acid) in primary cortical mixed cell cultures exposed to oxidotoxins are greatly improved compared to their parent compounds in the following rank-order: (1) PBN, (2) Trolox, and (3) lipoic acid. In contrast, the protective activity of indole-3-propionic acid was slightly decreased by grafting it on the amphiphilic carrier. Similar observations were made in in vivo experiments using aquatic invertebrate microorganisms, called rotifers, which were exposed to lethal concentrations of nonselective (H(2)O(2)) and mitochondria-selective (doxorubicin) oxidotoxins. The conclusion of these studies is that fluorinated amphiphilic PBN, Trolox, and lipoic acid derivatives exhibit very potent protective activities in in vitro and in vivo experiments. The findings demonstrated herein therefore strongly suggest that the amphiphilic character enhances the bioavailability of the antioxidants and allows for a selective targeting of mitochondria.