Acute Effect of a Saffron Extract (Safr'InsideTM) and Its Main Volatile Compound on the Stress Response in Healthy Young Men: A Randomized, Double Blind, Placebo-Controlled, Crossover Study.

According to animal studies, saffron and its main volatile compound safranal may reduce biological and behavioral signs of acute stress. However, little is known about its impact in humans. This study investigated the acute effect of a saffron extract and safranal on the biological and psychological stress responses in healthy men experiencing a laboratory stress procedure. In this double-blind, placebo-controlled, randomized, cross-over study, 19 volunteers aged 18-25 received a single dose of 30 mg saffron extract (Safr'InsideTM), 0.06 mg synthetic safranal, or a placebo on three visits separated by a 28-day washout. Thirteen minutes after administration, participants were exposed to the Maastricht acute stress test (MAST). Salivary cortisol and cortisone were collected from 15 min before the MAST (and pre-dose), 3 min before the MAST, and then 15, 30, 45, 60, and 75 min after the MAST, and stress and anxiety were measured using visual analogic scales. Compared to the placebo, stress and anxiety were significantly toned down after Safranal and Safr'InsideTM administration and coupled with a delay in the times to peak salivary cortisol and cortisone concentrations (p < 0.05). Safr'InsideTM and its volatile compound seem to improve psychological stress response in healthy men after exposure to a lab-based stressor and may modulate the biological stress response.

Circulating Human Serum Metabolites Derived from the Intake of a Saffron Extract (Safr'InsideTM) Protect Neurons from Oxidative Stress: Consideration for Depressive Disorders.

Increases in oxidative stress have been reported to play a central role in the vulnerability to depression, and antidepressant drugs may reduce increased oxidative stress in patients. Among the plants exerting anti-inflammatory and anti-oxidant properties, saffron, a spice derived from the flower of Crocus sativus, is also known for its positive effects on depression, potentially through its SSRI-like properties. However, the molecular mechanisms underlying these effects and their health benefits for humans are currently unclear. Using an original ex vivo clinical approach, we demonstrated for the first time that the circulating human metabolites produced following saffron intake (Safr'InsideTM) protect human neurons from oxidative-stress-induced neurotoxicity by preserving cell viability and increasing BNDF production. In particular, the metabolites significantly stimulated both dopamine and serotonin release. In addition, the saffron's metabolites were also able to protect serotonergic tone by inhibiting the expression of the serotonin transporter SERT and down-regulating serotonin metabolism. Altogether, these data provide new biochemical insights into the mechanisms underlying the beneficial impact of saffron on neuronal viability and activity in humans, in the context of oxidative stress related to depression.

Saffron Extract-Induced Improvement of Depressive-Like Behavior in Mice Is Associated with Modulation of Monoaminergic Neurotransmission.

Depressive disorders represent a major public health concern and display a continuously rising prevalence. Importantly, a large proportion of patients develops aversive side effects and/or does not respond properly to conventional antidepressants. These issues highlight the need to identify further therapeutic strategies, including nutritional approaches using natural plant extracts with known beneficial impacts on health. In that context, growing evidence suggests that saffron could be a particularly promising candidate. This preclinical study aimed therefore to test its antidepressant-like properties in mice and to decipher the underlying mechanisms by focusing on monoaminergic neurotransmission, due to its strong implication in mood disorders. For this purpose, the behavioral and neurobiochemical impact of a saffron extract, Safr'Inside™ (6.5 mg/kg per os) was measured in naïve mice. Saffron extract reduced depressive-like behavior in the forced swim test. This behavioral improvement was associated with neurobiological modifications, particularly changes in serotonergic and dopaminergic neurotransmission, suggesting that Safr'Inside™ may share common targets with conventional pharmacological antidepressants. This study provides useful information on the therapeutic relevance of nutritional interventions with saffron extracts to improve management of mood disorders.

Dietary vitamin A supplementation prevents early obesogenic diet-induced microbiota, neuronal and cognitive alterations.

BACKGROUND: Early consumption of obesogenic diets, rich in saturated fat and added sugar, is associated with a plethora of biological dysfunctions, at both peripheral and brain levels. Obesity is also linked to decreased vitamin A bioavailability, an essential molecule for brain plasticity and memory function. METHODS: Here we investigated in mice whether dietary vitamin A supplementation (VAS) could prevent some of the metabolic, microbiota, neuronal and cognitive alterations induced by obesogenic, high-fat and high-sugar diet (HFSD) exposure from weaning to adulthood, i.e. covering periadolescent period. RESULTS: As expected, VAS was effective in enhancing peripheral vitamin A levels as well as hippocampal retinoic acid levels, the active metabolite of vitamin A, regardless of the diet. VAS attenuated HFSD-induced excessive weight gain, without affecting metabolic changes, and prevented alterations of gut microbiota α-diversity. In HFSD-fed mice, VAS prevented recognition memory deficits but had no effect on aversive memory enhancement. Interestingly, VAS alleviated both HFSD-induced higher neuronal activation and lower glucocorticoid receptor phosphorylation in the hippocampus after training. CONCLUSION: Dietary VAS was protective against the deleterious effects of early obesogenic diet consumption on hippocampal function, possibly through modulation of the gut-brain axis.

Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study.

Polyphenols are promising nutritional bioactives exhibiting beneficial effect on age-related cognitive decline. This study evaluated the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on memory of healthy elderly subjects (60-70 years-old). A bicentric, randomized, double-blind, placebo-controlled trial was conducted with 215 volunteers receiving 600 mg/day of PEGB (containing 258 mg flavonoids) or a placebo for 6 months. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Secondary outcomes included verbal episodic and recognition memory (VRM) and working memory (SSP). There was no significant effect of PEGB on the PAL on the whole cohort. Yet, PEGB supplementation improved VRM-free recall. Stratifying the cohort in quartiles based on PAL at baseline revealed a subgroup with advanced cognitive decline (decliners) who responded positively to the PEGB. In this group, PEGB consumption was also associated with a better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. Urinary concentrations of specific flavan-3-ols metabolites were associated, at the end of the intervention, with the memory improvements. Our study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments.

Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition.

Ageing of the global population has become a public health concern with an important socio-economic dimension. Ageing is characterized by an increase in the concentration of inflammatory markers in the bloodstream, a phenomenon that has been termed "inflammageing". The inflammatory response is beneficial as an acute, transient reaction to harmful conditions, facilitating the defense, repair, turnover and adaptation of many tissues. However, chronic and low grade inflammation is likely to be detrimental for many tissues and for normal functions. We provide an overview of low grade inflammation (LGI) and determine the potential drivers and the effects of the "inflamed" phenotype observed in the elderly. We discuss the role of gut microbiota and immune system crosstalk and the gut-brain axis. Then, we focus on major health complications associated with LGI in the elderly, including mental health and wellbeing, metabolic abnormalities and infections. Finally, we discuss the possibility of manipulating LGI in the elderly by nutritional interventions. We provide an overview of the evidence that exists in the elderly for omega-3 fatty acid, probiotic, prebiotic, antioxidant and polyphenol interventions as a means to influence LGI. We conclude that slowing, controlling or reversing LGI is likely to be an important way to prevent, or reduce the severity of, age-related functional decline and the onset of conditions affecting health and well-being; that there is evidence to support specific dietary interventions as a strategy to control LGI; and that a continued research focus on this field is warranted.

Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome.

Mounting evidence shows that the gut microbiota, an important player within the gut-brain communication axis, can affect metabolism, inflammation, brain function and behavior. Interestingly, gut microbiota composition is known to be altered in patients with metabolic syndrome (MetS), who also often display neuropsychiatric symptoms. The use of prebiotics, which beneficially alters the microbiota, may therefore be a promising way to potentially improve physical and mental health in MetS patients. This hypothesis was tested in a mouse model of MetS, namely the obese and type-2 diabetic db/db mice, which display emotional and cognitive alterations associated with changes in gut microbiota composition and hippocampal inflammation compared to their lean db/+ littermates. We assessed the impact of chronic administration (8weeks) of prebiotics (oligofructose) on both metabolic (body weight, food intake, glucose homeostasis) and behavioral (increased anxiety-like behavior and impaired spatial memory) alterations characterizing db/db mice, as well as related neurobiological correlates, with particular attention to neuroinflammatory processes. Prebiotic administration improved excessive food intake and glycemic dysregulations (glucose tolerance and insulin resistance) in db/db mice. This was accompanied by an increase of plasma anti-inflammatory cytokine IL-10 levels and hypothalamic mRNA expression of the anorexigenic cytokine IL-1ß, whereas unbalanced mRNA expression of hypothalamic orexigenic (NPY) and anorexigenic (CART, POMC) peptides was unchanged. We also detected signs of improved blood-brain-barrier integrity in the hypothalamus of oligofructose-treated db/db mice (normalized expression of tight junction proteins ZO-1 and occludin). On the contrary, prebiotic administration did not improve behavioral alterations and associated reduction of hippocampal neurogenesis displayed by db/db mice, despite normalization of increased hippocampal IL-6 mRNA expression. Of note, we found a relationship between the effect of treatment on dentate gyrus neurons and spatial memory. These findings may prove valuable for introducing novel approaches to treat some of the comorbidities associated with MetS.

Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer.

Patients with cancer experience a host of behavioral alterations that include depression, fatigue, sleep disturbances, and cognitive dysfunction. These behavioral comorbidities are apparent throughout the process of diagnosis and treatment for cancer and can persist well into the survivorship period. There is a rich literature describing potential consequences of behavioral comorbidities in patients with cancer including impaired quality of life, reduced treatment adherence, and increased disease-related morbidity and mortality. Medical complications of cancer and its treatment such as anemia, thyroid dysfunction, and the neurotoxicity of cancer chemotherapeutic agents account in part for these behavioral changes. Nevertheless, recent advances in the neurosciences and immunology/oncology have revealed novel insights into additional pathophysiologic mechanisms that may significantly contribute to the development of cancer-related behavioral changes. Special attention has been focused on immunologic processes, specifically activation of innate immune inflammatory responses and their regulation by neuroendocrine pathways, which, in turn, influence CNS functions including neurotransmitter metabolism, neuropeptide function, sleep-wake cycles, regional brain activity, and, ultimately, behavior. Further understanding of these immunologic influences on the brain provides a novel conceptual framework for integrating the wide spectrum of behavioral alterations that occur in cancer patients and may reveal a more focused array of translational targets for therapeutic interventions and future research. Such developments warrant complementary advances in identification of cancer patients at risk as well as those currently suffering, including an increased emphasis on the status of behavior as a "sixth vital sign" to be assessed in all cancer patients throughout their disease encounter.

Identification and treatment of symptoms associated with inflammation in medically ill patients.

Medically ill patients present with a high prevalence of non-specific comorbid symptoms including pain, sleep disorders, fatigue and cognitive and mood alterations that is a leading cause of disability. However, despite major advances in the understanding of the immune-to-brain communication pathways that underlie the pathophysiology of these symptoms in inflammatory conditions, little has been done to translate this newly acquired knowledge to the clinics and to identify appropriate therapies. In a multidisciplinary effort to address this problem, clinicians and basic scientists with expertise in areas of inflammation, psychiatry, neurosciences and psychoneuroimmunology were brought together in a specialized meeting organized in Bordeaux, France, on May 28-29, 2007. These experts considered key questions in the field, in particular those related to identification and quantification of the predominant symptoms associated with inflammation, definition of systemic and central markers of inflammation, possible domains of intervention for controlling inflammation-associated symptoms, and relevance of animal models of inflammation-associated symptoms. This resulted in a number of recommendations that should improve the recognition and management of inflammation-associated symptoms in medically ill patients.

Plasma homocysteine and immune activation in patients with malignant melanoma undergoing treatment with IFN-alpha.

Immune activation and cell proliferation may contribute to the development of increased homocysteine concentrations in patients with malignant diseases. In this study, we investigated the effect of interferon-alpha (IFN-alpha) on plasma homocysteine concentrations in patients being treated for malignant melanoma. In parallel, neopterin formation and tryptophan degradation were monitored to assess the capacity of IFN-alpha to activate macrophages. Plasma concentrations of homocysteine, folate, and vitamin B(12) were determined in 15 patients with malignant melanoma during 12 weeks of high-dose IFN-alpha therapy. Concurrently, concentrations of neopterin, tryptophan, and kynurenine were measured, and the kynurenine/tryptophan ratio (kyn/trp) was calculated. Homocysteine and folate concentrations during treatment with IFN-alpha did not differ from baseline. In contrast, significant increases in neopterin formation and tryptophan degradation were apparent during IFN-alpha therapy. Plasma concentrations of vitamin B(12) and cysteine also increased. These results indicate that IFN-alpha directly activates macrophages to release neopterin and to degrade tryptophan, but obviously treatment with INF-alpha did not affect homocysteine metabolism.